iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://doi.org/10.1208/s12248-020-00536-y
The Role of Alcohol Dehydrogenase in Drug Metabolism: Beyond Ethanol Oxidation | The AAPS Journal Skip to main content

Advertisement

Springer Nature Link
Log in

The Role of Alcohol Dehydrogenase in Drug Metabolism: Beyond Ethanol Oxidation

  • Review Article
  • Theme: Celebrating Women in the Pharmaceutical Sciences
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Alcohol dehydrogenases (ADHs) are most known for their roles in oxidation and elimination of ethanol. Although less known, ADHs also play a critical role in the metabolism of a number of drugs and metabolites that contain alcohol functional groups, such as abacavir (HIV/AIDS), hydroxyzine (antihistamine), and ethambutol (antituberculosis). ADHs consist of 7 gene family numbers and several genetic polymorphic forms. ADHs are cytosolic enzymes that are most abundantly found in the liver, although also present in other tissues including gastrointestinal tract and adipose. Marked species differences exist for ADHs including genes, proteins, enzymatic activity, and tissue distribution. The active site of ADHs is relatively small and cylindrical in shape. This results in somewhat narrow substrate specificity. Secondary alcohols are generally poor substrates for ADHs. In vitro-in vivo correlations for ADHs have not been established, partly due to insufficient clinical data. Fomepizole (4-methylpyrazole) is a nonspecific ADH inhibitor currently being used as an antidote for the treatment of methanol and ethylene glycol poisoning. Fomepizole also has the potential to treat intoxication of other substances of abuse by inhibiting ADHs to prevent formation of toxic metabolites. ADHs are inducible through farnesoid X receptor (FXR) and other transcription factors. Drug-drug interactions have been observed in the clinic for ADHs between ethanol and therapeutic drugs, and between fomepizole and ADH substrates. Future research in this area will provide additional insights about this class of complex, yet fascinating enzymes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

ADHs:

Alcohol dehydrogenases

AIDS:

Acquired immunodeficiency syndrome

ALDHs:

Aldehyde dehydrogenases

AUC:

Area under the curve

BMI:

Body mass index

CB1 and CB2:

Cannabinoid receptors 1 and 2

CDCA:

Chenodeoxycholic acid

C/EBPα and β:

CCAAT-enhancer binding proteins α and β

Cmax :

Maximum concentration

CNS:

Central nervous system

COX-2:

Cyclooxygenase-2

CTF:

CAAT box-binding transcription factor

CYP:

Cytochrome P450

DEA:

Drug enforcement agency

DDI:

Drug-drug interaction

[E]:

Enzyme concentration

[E•NAD+]:

Concentration of NAD+ bound enzyme

FDA:

The Food and Drug Administration

FXR:

Farnesoid X receptor

GIT:

Gastrointestinal tract;

HIV:

Human immunodeficiency virus

HNF-1:

Hepatocyte nuclear factor 1

HOGO:

Human Genome Organisation

5-HT:

5-Hydroxytryptamine receptors

IC50 :

Half maximal inhibitory concentration

ISEF:

Intersystem extrapolation factor

IVIVE:

In vitro-in vivo extrapolation

kDa:

Kilodalton

Ki :

Inhibition constant

Km :

Michaelis-Menten constant

LC-MS/MS:

Liquid chromatography with tandem mass spectrometry

Log P:

Lipophilicity

MDRs:

Medium-chain dehydrogenases/reductases

4-MP:

4-Methylpyrazole

mRNA:

Messenger ribonucleic acid

NAD+ :

Nicotinamide adenine dinucleotide

NADH:

Reduced form of nicotinamide adenine dinucleotide

NASH:

Nonalcoholic steatohepatitis

NBP:

Butylphthalide or l-3-n-butylphthalide

NF-1:

Nuclear factor-1

NSAID:

Anti-inflammatory drug

SSRI:

Selective serotonin reuptake inhibitor

OCD:

Obsessive compulsive disorder

PEG:

Polyethylene glycols

PK:

Pharmacokinetics

P-gp:

P-glycoprotein

RAF:

Relative activity factor

SGLT2:

Sodium-glucose co-transporter 2

T2DM:

Type 2 diabetes mellitus

UGT:

UDP-glucuronosyltransferase

USF:

Upstream stimulatory factor

References

  1. Edenberg HJ, McClintick JN. Alcohol dehydrogenases, aldehyde dehydrogenases, and alcohol use disorders: a critical review. Alcohol Clin Exp Res. 2018;42(12):2281–97. https://doi.org/10.1111/acer.13904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Edenberg HJ, Bosron WF. Alcohol dehydrogenases. In: McQueen CA, editor. Comprehensive toxicology. 3nd ed. Oxford: Elsevier; 2018. p. 126–39.

    Google Scholar 

  3. Bhatt DK, Gaedigk A, Pearce RE, Leeder JS, Prasad B. Age-dependent protein abundance of cytosolic alcohol and aldehyde dehydrogenases in human liver. Drug Metab Dispos. 2017;45(9):1044–8,S1-S34. https://doi.org/10.1124/dmd.117.076463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Parkinson A, Ogilvie BW, Buckley DB, Kazmi F, Parkinson O. Biotransformation of xenobiotics. In: Klaassen C, editor. The basic science of poisons. 9th ed. New York: McGraw-Hill Education; 2018. p. 243.

    Google Scholar 

  5. Yang Z-N, Bosron WF, Hurley TD. Structure of human χχ alcohol dehydrogenase: a glutathione-dependent formaldehyde dehydrogenase. J Mol Biol. 1997;265(3):330–43. https://doi.org/10.1006/jmbi.1996.0731.

    Article  CAS  PubMed  Google Scholar 

  6. Duester G, Farres J, Felder MR, Holmes RS, Hoog J-O, Pares X, et al. Recommended nomenclature for the vertebrate alcohol dehydrogenase gene family. Biochem Pharmacol. 1999;58(3):389–95. https://doi.org/10.1016/S0006-2952(99)00065-9.

    Article  CAS  PubMed  Google Scholar 

  7. Ostberg LJ, Persson B, Persson B, Hoog J-O. Computational studies of human class V alcohol dehydrogenase - the odd sibling. BMC Biochem. 2016;17(1):16.

    PubMed  PubMed Central  Google Scholar 

  8. Edenberg HJ. The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health. 2007;30(1):5–13.

    PubMed  PubMed Central  Google Scholar 

  9. Deltour L, Foglio MH, Duester G. Metabolic deficiencies in alcohol dehydrogenase Adh1, Adh3, and Adh4 null mutant mice. Overlapping roles of Adh1 and Adh4 in ethanol clearance and metabolism of retinol to retinoic acid. J Biol Chem. 1999;274(24):16796–801. https://doi.org/10.1074/jbc.274.24.16796.

    Article  CAS  PubMed  Google Scholar 

  10. Parkin G. Synthetic analogues relevant to the structure and function of zinc enzymes. Chem Rev (Washington, DC, U S). 2004;104(2):699–767. https://doi.org/10.1021/cr0206263.

    Article  CAS  Google Scholar 

  11. Crichton R. Biological inorganic chemistry: a new introduction to molecular structure and function. Chapter 12. Zinc: Lewis Acid and Gene Regulator. 3rd ed2018.

  12. Auld DS. Zinc coordination sphere in biochemical zinc sites. BioMetals. 2001;14(3–4):271–313.

    CAS  PubMed  Google Scholar 

  13. Eklund H, Braenden CI. Alcohol dehydrogenase. Biol Macromol Assem. 1987;3:73–142.

    CAS  Google Scholar 

  14. Eklund H, Samama JP, Wallen L, Braenden CI, Aakeson A, Jones TA. Structure of a triclinic ternary complex of horse liver alcohol dehydrogenase at 2.9 Å resolution. J Mol Biol. 1981;146(4):561–87. https://doi.org/10.1016/0022-2836(81)90047-4.

    Article  CAS  PubMed  Google Scholar 

  15. Klinman JP. Probes of mechanism and transition-state structure in the alcohol dehydrogenase reaction. CRC Crit Rev Biochem. 1981;10(1):39–78. https://doi.org/10.3109/10409238109114635.

    Article  CAS  PubMed  Google Scholar 

  16. Hurley TD, Bosron WF, Hamilton JA, Amzel LM. Structure of human β1β1 alcohol dehydrogenase: catalytic effects of non-active-site substitutions. Proc Natl Acad Sci U S A. 1991;88(18):8149–53. https://doi.org/10.1073/pnas.88.18.8149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hurley TD, Bosron WF, Stone CL, Amzel LM. Structures of three human β alcohol dehydrogenase variants. Correlations with their functional differences. J Mol Biol. 1994;239(3):415–29. https://doi.org/10.1006/jmbi.1994.1382.

    Article  CAS  PubMed  Google Scholar 

  18. Davis GJ, Bosron WF, Stone CL, Owusu-Dekyi K, Hurley TD. X-ray structure of human beta3beta3 alcohol dehydrogenase. The contribution of ionic interactions to coenzyme binding. J Biol Chem. 1996;271(29):17057–61.

    CAS  PubMed  Google Scholar 

  19. Xie P, Parsons SH, Speckhard DC, Bosron WF, Hurley TD. X-ray structure of human class IV sigmasigma alcohol dehydrogenase. Structural basis for substrate specificity. J Biol Chem. 1997;272(30):18558–63.

    CAS  PubMed  Google Scholar 

  20. Niederhut MS, Gibbons BJ, Perez-Miller S, Hurley TD. Three-dimensional structures of the three human class I alcohol dehydrogenases. Protein Sci. 2001;10(4):697–706. https://doi.org/10.1110/ps.45001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Eklund H, Plapp BV, Samama JP, Braenden CI. Binding of substrate in a ternary complex of horse liver alcohol dehydrogenase. J Biol Chem. 1982;257(23):14349–58.

    CAS  PubMed  Google Scholar 

  22. Gibbons BJ, Hurley TD. Structure of three class I human alcohol dehydrogenases complexed with Isoenzyme specific Formamide inhibitors. Biochemistry. 2004;43(39):12555–62. https://doi.org/10.1021/bi0489107.

    Article  CAS  PubMed  Google Scholar 

  23. Stone CL, Li TK, Bosron WF. Stereospecific oxidation of secondary alcohols by human alcohol dehydrogenases. J Biol Chem. 1989;264(19):11112–6.

    CAS  PubMed  Google Scholar 

  24. McEvily AJ, Holmquist B, Auld DS, Vallee BL. 3β-Hydroxy-5β-steroid dehydrogenase activity of human liver alcohol dehydrogenase is specific to γ-subunits. Biochemistry. 1988;27(12):4284–8. https://doi.org/10.1021/bi00412a013.

    Article  CAS  PubMed  Google Scholar 

  25. Hansch C, Schaeffer J, Kerley R. Alcohol dehydrogenase structure-activity relationships. J Biol Chem. 1972;247(14):4703–10.

    CAS  PubMed  Google Scholar 

  26. Carrigan MA, Uryasev O, Davis RP, Zhai LM, Hurley TD, Benner SA. The natural history of class I primate alcohol dehydrogenases includes gene duplication, gene loss and gene conversion. PLoS One. 2012;7(7):e41175. https://doi.org/10.1371/journal.pone.0041175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Szalai G, Duester G, Friedman R, Jia H, Lin S, Roe BA, et al. Organization of six functional mouse alcohol dehydrogenase genes on two overlapping bacterial artificial chromosomes. Eur J Biochem. 2002;269(1):224–32. https://doi.org/10.1046/j.0014-2956.2001.02642.x.

    Article  CAS  PubMed  Google Scholar 

  28. Hur MW, Edenberg HJ. Cloning and characterization of the ADH5 gene encoding human alcohol dehydrogenase 5, formaldehyde dehydrogenase. Gene. 1992;121(2):305–11. https://doi.org/10.1016/0378-1119(92)90135-C.

    Article  CAS  PubMed  Google Scholar 

  29. Matsuo Y, Yokoyama S. Cloning and sequencing of a processed pseudogene derived from a human class III alcohol dehydrogenase gene. Am J Hum Genet. 1990;46(1):85–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Winnier DA, Fourcaudot M, Norton L, Abdul-Ghani MA, Hu SL, Farook VS, et al. Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in mexican americans from the veterans administration genetic epidemiology study (VAGES). PLoS One. 2015;10(4):e0119941/1-e/26. https://doi.org/10.1371/journal.pone.0119941.

    Article  CAS  Google Scholar 

  31. Jelski W, Chrostek L, Szmitkowski M, Laszewicz W. Activity of class I, II, III, and IV alcohol dehydrogenase isoenzymes in human gastric mucosa. Dig Dis Sci. 2002;47(7):1554–7.

    CAS  PubMed  Google Scholar 

  32. Allali-Hassani A, Martinez SE, Peralba JM, Vaglenova J, Vidal F, Richart C, et al. Alcohol dehydrogenase of human and rat blood vessels. Role in ethanol metabolism. [Erratum to document cited in CA126:208441]. FEBS Lett. 1997;411(2,3):395. https://doi.org/10.1016/S0014-5793(97)00151-8.

    Article  CAS  Google Scholar 

  33. Allali-Hassani A, Martinez SE, Peralba JM, Vaglenova J, Vidal F, Richart C, et al. Alcohol dehydrogenase of human and rat blood vessels. Role in ethanol metabolism. FEBS Lett. 1997;405(1):26–30. https://doi.org/10.1016/S0014-5793(97)00151-8.

    Article  CAS  PubMed  Google Scholar 

  34. Mumenthaler MS, Taylor JL, O'Hara R, Yesavage JA. Gender differences in moderate drinking effects. Alcohol Res Health. 1999;23(1):55–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Baraona E, Abittan CS, Dohmen K, Moretti M, Pozzato G, Chayes ZW, et al. Gender differences in pharmacokinetics of alcohol. Alcohol Clin Exp Res. 2001;25(4):502–7. https://doi.org/10.1111/j.1530-0277.2001.tb02242.x.

    Article  CAS  PubMed  Google Scholar 

  36. Seitz HK, Egerer G, Simanowski UA, Waldherr R, Eckey R, Agarwal DP, et al. Human gastric alcohol dehydrogenase activity: effect of age, sex, and alcoholism. Gut. 1993;34(10):1433–7. https://doi.org/10.1136/gut.34.10.1433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Parlesak A, Billinger MH-U, Bode C, Bode JC. Gastric alcohol dehydrogenase activity in man: influence of gender, age, alcohol consumption and smoking in a Caucasian population. Alcohol Alcohol (Oxford, U K). 2002;37(4):388–93. https://doi.org/10.1093/alcalc/37.4.388.

    Article  CAS  Google Scholar 

  38. Frezza M, di Padova C, Pozzato G, Terpin M, Baraona E, Lieber CS. High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. N Engl J Med. 1990;322(2):95–9.

    CAS  PubMed  Google Scholar 

  39. Maly IP, Sasse D. Intraacinar profiles of alcohol dehydrogenase and aldehyde dehydrogenase activities in human liver. Gastroenterology. 1991;101(6):1716–23. https://doi.org/10.1016/0016-5085(91)90412-E.

    Article  CAS  PubMed  Google Scholar 

  40. Chrostek L, Jelski W, Szmitkowski M, Puchalski Z. Gender-related differences in hepatic activity of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in humans. J Clin Lab Anal. 2003;17(3):93–6. https://doi.org/10.1002/jcla.10076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rachamin G, Macdonald JA, Wahid S, Clapp JJ, Khanna JM, Israel Y. Modulation of alcohol dehydrogenase and ethanol metabolism by sex hormones in the spontaneously hypertensive rat. Effect of chronic ethanol administration. Biochem J. 1980;186(2):483–90. https://doi.org/10.1042/bj1860483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Simon FR, Fortune J, Iwahashi M, Sutherland E. Sexual dimorphic expression of ADH in rat liver: importance of the hypothalamic-pituitary-liver axis. Am J Physiol. 2002;283(3, Pt. 1):G646–G55.

    CAS  Google Scholar 

  43. Quintanilla ME, Tampier L, Sapag A, Gerdtzen Z, Israel Y. Sex differences, alcohol dehydrogenase, acetaldehyde burst, and aversion to ethanol in the rat: a systems perspective. Am J Physiol. 2007;293(2, Pt. 1):E531–E7. https://doi.org/10.1152/ajpendo.00187.2007.

    Article  CAS  Google Scholar 

  44. Rachamin G, Israel Y. Sex differences in hepatic alcohol dehydrogenase activity in animal species. Biochem Pharmacol. 1985;34(13):2385–6. https://doi.org/10.1016/0006-2952(85)90798-1.

    Article  CAS  PubMed  Google Scholar 

  45. DiPadova C, Worner TM, Julkunen RJ, Lieber CS. Effects of fasting and chronic alcohol consumption on the first-pass metabolism of ethanol. Gastroenterology. 1987;92(5 Pt 1):1169–73.

    CAS  PubMed  Google Scholar 

  46. Cederbaum AI. Alcohol metabolism. Clin Liver Dis. 2012;16(4):667–85.

    PubMed  PubMed Central  Google Scholar 

  47. Oneta CM, Simanowski UA, Martinez M, Allali-Hassani A, Pares X, Homann N, et al. First pass metabolism of ethanol is strikingly influenced by the speed of gastric emptying. Gut. 1998;43(5):612–9. https://doi.org/10.1136/gut.43.5.612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bosron WF, Li TK. Catalytic properties of human liver alcohol dehydrogenase isoenzymes. Enzyme. 1987;37(1–2):19–28. https://doi.org/10.1159/000469238.

    Article  CAS  PubMed  Google Scholar 

  49. Ehlers CL, Gilder DA, Harris L, Carr L. Association of the ADH2*3 allele with a negative family history of alcoholism in African American young adults. Alcohol Clin Exp Res. 2001;25(12):1773–7. https://doi.org/10.1111/j.1530-0277.2001.tb02189.x.

    Article  CAS  PubMed  Google Scholar 

  50. Li H, Toth E, Cherrington NJ. Alcohol metabolism in the progression of human nonalcoholic steatohepatitis. Toxicol Sci. 2018;164(2):428–38. https://doi.org/10.1093/toxsci/kfy106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Baker SS, Baker RD, Liu W, Nowak NJ, Zhu L. Role of alcohol metabolism in non-alcoholic steatohepatitis. PLoS One. 2010;5(3):e9570.

    PubMed  PubMed Central  Google Scholar 

  52. Wei SZ, Xu L, Schooling CM, Jiang CQ, Cheng KK, Liu B, et al. Effect of alcohol and aldehyde dehydrogenase gene polymorphisms on alcohol-associated hypertension: the Guangzhou Biobank Cohort Study. Hypertens Res. 2013;36(8):741–6. https://doi.org/10.1038/hr.2013.23.

    Article  CAS  Google Scholar 

  53. Orywal K, Jelski W, Werel T, Szmitkowski M. The activity of class I, II, III and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in the sera of bladder cancer patients. Acta Biochim Pol. 2017;64(1):81–4. https://doi.org/10.18388/abp.2016_1289.

    Article  CAS  PubMed  Google Scholar 

  54. Laniewska-Dunaj M, Jelski W, Orywal K, Kochanowicz J, Rutkowski R, Szmitkowski M. The activity of class I, II, III and IV of alcohol dehydrogenase (ADH) Isoenzymes and aldehyde dehydrogenase (ALDH) in brain Cancer. Neurochem Res. 2013;38(7):1517–21. https://doi.org/10.1007/s11064-013-1053-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Orywal K, Jelski W, Zdrodowski M, Szmitkowski M. The activity of class I, II, III and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in cervical cancer. Clin Biochem. 2011;44(14–15):1231–4. https://doi.org/10.1016/j.clinbiochem.2011.07.004.

    Article  CAS  PubMed  Google Scholar 

  56. Jelski W, Zalewski B, Chrostek L, Szmitkowski M. The activity of class I, II, III, and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in colorectal Cancer. Dig Dis Sci. 2004;49(6):977–81. https://doi.org/10.1023/B:DDAS.0000034557.23322.e0.

    Article  CAS  PubMed  Google Scholar 

  57. Orywal K, Jelski W, Zdrodowski M, Szmitkowski M. The activity of class I, II, III, and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in endometrial cancer. J Clin Lab Anal. 2010;24(5):334–9.

    PubMed  PubMed Central  Google Scholar 

  58. Jelski W, Zalewski B, Szmitkowski M. The activity of class I, II, III, and IV alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) in liver cancer. Dig Dis Sci. 2008;53(9):2550–5. https://doi.org/10.1007/s10620-007-0153-2.

    Article  CAS  PubMed  Google Scholar 

  59. Orywal K, Jelski W, Werel T, Szmitkowski M. The activity of class I, II, III and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in renal cell carcinoma. Exp Mol Pathol. 2015;98(3):403–6. https://doi.org/10.1016/j.yexmp.2015.03.012.

    Article  CAS  PubMed  Google Scholar 

  60. Orywal K, Jelski W, Zdrodowski M, Szmitkowski M. The activity of class I, II, III and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in ovarian cancer and ovarian cysts. Adv Med Sci. 2013;58(2):216–20. https://doi.org/10.2478/ams-2013-0012.

    Article  CAS  PubMed  Google Scholar 

  61. Jelski W, Orywal K, Panek B, Gacko M, Mroczko B, Szmitkowski M. The activity of class I, II, III and IV of alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) in the wall of abdominal aortic aneurysms. Exp Mol Pathol. 2009;87(1):59–62. https://doi.org/10.1016/j.yexmp.2009.03.001.

    Article  CAS  PubMed  Google Scholar 

  62. Jelski W, Chrostek L, Szmitkowski M, Markiewicz W. The activity of class I, II, III and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in breast cancer. Clin Exp Med. 2006;6(2):89–93. https://doi.org/10.1007/s10238-006-0101-z.

    Article  CAS  PubMed  Google Scholar 

  63. Jelski W, Kozlowski M, Laudanski J, Niklinski J, Szmitkowski M. The activity of class I, II, III, and IV alcohol dehydrogenase (ADH) Isoenzymes and aldehyde dehydrogenase (ALDH) in esophageal cancer. Dig Dis Sci. 2009;54(4):725–30. https://doi.org/10.1007/s10620-008-0422-8.

    Article  CAS  PubMed  Google Scholar 

  64. Jelski W, Chrostek L, Szmitkowski M. The activity of class I, II, III, and IV of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in pancreatic cancer. Pancreas (Hagerstown, MD, U S). 2007;35(2):142–6. https://doi.org/10.1097/MPA.0b013e318053eae2.

    Article  CAS  Google Scholar 

  65. Buervenich S, Sydow O, Carmine A, Zhang Z, Anvret M, Olson L. Alcohol dehydrogenase alleles in Parkinson’s disease. Mov Disord. 2000;15(5):813–8.

    CAS  PubMed  Google Scholar 

  66. Buervenich S, Carmine A, Galter D, Shahabi HN, Johnels B, Holmberg B, et al. A rare truncating mutation in ADH1C (G78Stop) shows significant association with Parkinson disease in a large international sample. Arch Neurol. 2005;62(1):74–8.

    PubMed  Google Scholar 

  67. Tan EK, Nagamitsu S, Matsuura T, Khajavi M, Jankovic J, Ondo W, et al. Alcohol dehydrogenase polymorphism and Parkinson's disease. Neurosci Lett. 2001;305(1):70–2. https://doi.org/10.1016/S0304-3940(01)01770-0.

    Article  CAS  PubMed  Google Scholar 

  68. Kim JJ, Bandres-Ciga S, Blauwendraat C, Gan-Or Z. No genetic evidence for involvement of alcohol dehydrogenase genes in risk for Parkinson’s disease. Neurobiol Aging. 2020;87:140.e19–22. https://doi.org/10.1016/j.neurobiolaging.2019.11.006.

    Article  CAS  Google Scholar 

  69. Seitz HK, Oneta CM. Gastrointestinal alcohol dehydrogenase. Nutr Rev. 1998;56(2 Pt 1):52–60.

    CAS  PubMed  Google Scholar 

  70. Grilo NM, Antunes AMM, Caixas U, Marinho AT, Charneira C, Conceicao Oliveira M, et al. Monitoring abacavir bioactivation in humans: screening for an aldehyde metabolite. Toxicol Lett. 2013;219(1):59–64. https://doi.org/10.1016/j.toxlet.2013.02.021.

    Article  CAS  PubMed  Google Scholar 

  71. Walsh JS, Reese MJ, Thurmond LM. The metabolic activation of abacavir by human liver cytosol and expressed human alcohol dehydrogenase isozymes. Chem Biol Interact. 2002;142(1–2):135–54. https://doi.org/10.1016/S0009-2797(02)00059-5.

    Article  CAS  PubMed  Google Scholar 

  72. McDowell JA, Chittick GE, Stevens CP, Edwards KD, Stein DS. Pharmacokinetic interaction of abacavir (1592U89) and ethanol in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2000;44(6):1686–90. https://doi.org/10.1128/AAC.44.6.1686-1690.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Liakoni E, Gugelmann H, Dempsey DA, Wiegand TJ, Havel C, Jacob P, et al. Butanediol conversion to gamma-hydroxybutyrate markedly reduced by the alcohol dehydrogenase blocker fomepizole. Clin Pharmacol Ther (Hoboken, NJ, U S). 2019;105(5):1196–203. https://doi.org/10.1002/cpt.1306.

    Article  CAS  Google Scholar 

  74. Anderson I, Kim-Katz S, Dyer J, Blanc P. The impact of gamma hydroxybutyrate (GHB) legal restrictions on patterns of use: results from an international survey. Drugs (Abingdon Engl). 2010;17(5):455–69.

    Google Scholar 

  75. Abdoulaye IA, Guo YJ, et al. BioMed Res Int. 2016:5012341/1−/9. https://doi.org/10.1155/2016/5012341.

  76. Diao X, Deng P, Xie C, Li X, Zhong D, Zhang Y, et al. Metabolism and pharmacokinetics of 3-n-butylphthalide (NBP) in humans: the role of cytochrome P450s and alcohol dehydrogenase in biotransformation. Drug Metab Dispos. 2013;41(2):430–44. https://doi.org/10.1124/dmd.112.049684.

    Article  CAS  PubMed  Google Scholar 

  77. Deng P, You T, Chen X, Yuan T, Huang H, Zhong D. Identification of amiodarone metabolites in human bile by ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry. Drug Metab Dispos. 2011;39(6):1058–69. https://doi.org/10.1124/dmd.110.037671.

    Article  CAS  PubMed  Google Scholar 

  78. Holm NB, Noble C, Linnet K. JWH-018 ω-OH, a shared hydroxy metabolite of the two synthetic cannabinoids JWH-018 and AM-2201, undergoes oxidation by alcohol dehydrogenase and aldehyde dehydrogenase enzymes in vitro forming the carboxylic acid metabolite. Toxicol Lett. 2016;259:35–43. https://doi.org/10.1016/j.toxlet.2016.07.007.

    Article  CAS  PubMed  Google Scholar 

  79. Chimalakonda KC, Moran CL, Kennedy PD, Endres GW, Uzieblo A, Dobrowolski PJ, et al. Solid-phase extraction and quantitative measurement of omega and omega-1 metabolites of JWH-018 and JWH-073 in human urine. Anal Chem (Washington, DC, U S). 2011;83(16):6381–8. https://doi.org/10.1021/ac201377m.

    Article  CAS  Google Scholar 

  80. Castaneto MS, Scheidweiler KB, Gandhi A, Wohlfarth A, Klette KL, Martin TM, et al. Quantitative urine confirmatory testing for synthetic cannabinoids in randomly collected urine specimens. Drug Test Anal. 2015;7(6):483–93. https://doi.org/10.1002/dta.1709.

    Article  CAS  PubMed  Google Scholar 

  81. Moran CL, Le V-H, Chimalakonda KC, Smedley AL, Lackey FD, Owen SN, et al. Quantitative measurement of JWH-018 and JWH-073 metabolites excreted in human urine. Anal Chem (Washington, DC, U S). 2011;83(11):4228–36. https://doi.org/10.1021/ac2005636.

    Article  CAS  Google Scholar 

  82. Clemett D, Goa KL. Celecoxib: a review of its use in osteoarthritis, rheumatoid arthritis and acute pain. Drugs. 2000;59(4):957–80.

    CAS  PubMed  Google Scholar 

  83. Gong L, Thorn CF, Bertagnolli MM, Grosser T, Altman RB, Klein TE. Celecoxib pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2012;22(4):310–8. https://doi.org/10.1097/FPC.0b013e32834f94cb.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Paulson SK, Hribar JD, Liu NWK, Hajdu E, Bible RH Jr, Piergies A, et al. Metabolism and excretion of [14C]celecoxib in healthy male volunteers. Drug Metab Dispos. 2000;28(3):308–14.

    CAS  PubMed  Google Scholar 

  85. Sandberg M, Yasar U, Stroemberg P, Hoeoeg J-O, Eliasson E. Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase. Br J Clin Pharmacol. 2002;54(4):423–9. https://doi.org/10.1046/j.1365-2125.2002.01660.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. de Jonge ME, Huitema ADR, Rodenhuis S, Beijnen JH. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet. 2005;44(11):1135–64. https://doi.org/10.2165/00003088-200544110-00003.

    Article  PubMed  Google Scholar 

  87. Breda M, Strolin Benedetti M, Bani M, Pellizzoni C, Poggesi I, Brianceschi G, et al. Effect of rifabutin on ethambutol pharmacokinetics in healthy volunteers. Pharmacol Res. 1999;40(4):351–6. https://doi.org/10.1006/phrs.1999.0526.

    Article  CAS  PubMed  Google Scholar 

  88. Peets EA, Sweeney WM, Place VA, Buyske DA. The absorption, excretion, and metabolic fate of ethambutol in man. Am Rev Respirat Diseases. 1965;91(1):51–8.

    CAS  Google Scholar 

  89. Peets EA. An effect of ethambutol, 2,2′-(ethylenediimino)di-l-butanol, on the structure and activity of alcohol dehydrogenase. Nature (London, U K). 1965;205(4968):241–2. https://doi.org/10.1038/205241a0.

    Article  CAS  Google Scholar 

  90. Lieber CS. The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role. Drug Metab Rev. 2004;36(3–4):511–29. https://doi.org/10.1081/DMR-200033441.

    Article  CAS  PubMed  Google Scholar 

  91. Hurley TD, Edenberg HJ, Li T-K. The pharmacogenomics of alcoholism. In: Licinio J, Wong M-L, editors. Pharmacogenomics: the search for individualized therapies. Weinheim: Wiley-VCH; 2002. p. 417–41.

    Google Scholar 

  92. Takeshita T, Mao X-Q, Morimoto K. The contribution of polymorphism in the alcohol dehydrogenase β subunit to alcohol sensitivity in a Japanese population. Hum Genet. 1996;97(4):409–13. https://doi.org/10.1007/BF02267057.

    Article  CAS  PubMed  Google Scholar 

  93. Garcia-Martin E, Martinez C, Serrador M, Alonso-Navarro H, Navacerrada F, Agundez JAG, et al. Alcohol dehydrogenase 2 genotype and risk for migraine. Headache. 2010;50(1):85–91.

    PubMed  Google Scholar 

  94. Walters RK, Adams MJ, Adkins AE, Aliev F, Bacanu S-A, Batzler A, et al. Trans-ancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders. bioRxiv, Genet. 2018:1–34. https://doi.org/10.1101/257311.

  95. Marchitti SA, Brocker C, Stagos D, Vasiliou V. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert Opin Drug Metab Toxicol. 2008;4(6):697–720. https://doi.org/10.1517/17425255.4.6.697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Setshedi M, Wands JR. Monte SMdl. Acetaldehyde adducts in alcoholic liver disease. Oxidative Med Cell Longev. 2010;3(3):178–85.

    Google Scholar 

  97. Leppik IE, Dreifuss FE, Pledger GW, Graves NM, Santilli N, Drury I, et al. Felbamate for partial seizures: results of a controlled clinical trial. Neurology. 1991;41(11):1785–9.

    CAS  PubMed  Google Scholar 

  98. Thakkar K, Billa G, Rane J, Chudasama H, Goswami S, Shah R. The rise and fall of felbamate as a treatment for partial epilepsy - aplastic anemia and hepatic failure to blame? Expert Rev Neurother. 2015;15(12):1373–5. https://doi.org/10.1586/14737175.2015.1113874.

    Article  CAS  PubMed  Google Scholar 

  99. Dieckhaus CM, Miller TA, Sofia RD, Macdonald TL. A mechanistic approach to understanding species differences in felbamate bioactivation: relevance to drug-induced idiosyncratic reactions. Drug Metab Dispos. 2000;28(7):814–22.

    CAS  PubMed  Google Scholar 

  100. Foti RS, Dalvie DK. Cytochrome P450 and non-cytochrome P450 oxidative metabolism: contributions to the pharmacokinetics, safety, and efficacy of xenobiotics. Drug Metab Dispos. 2016;44(8):1229–45. https://doi.org/10.1124/dmd.116.071753.

    Article  CAS  PubMed  Google Scholar 

  101. Strolin Benedetti M, Whomsley R, Baltes E. Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics. Expert Opin Drug Metab Toxicol. 2006;2(6):895–921. https://doi.org/10.1517/17425255.2.6.895.

    Article  CAS  PubMed  Google Scholar 

  102. Ma S, Takahashi RH, Ma Y, Bobba S, Zhang D, Khojasteh SC. Non-CYP drug metabolizing enzymes and their reactions. In: Pearson P, Wienkers LC, editors. Handbook of drug metabolism. 3rd ed. Boca Raton: CRC Press; 2019.

    Google Scholar 

  103. Thompson CD, Kinter MT, Macdonald TL. Synthesis and in vitro reactivity of 3-carbamoyl-2-phenylpropionaldehyde and 2-phenylpropenal: putative reactive metabolites of Felbamate. Chem Res Toxicol. 1996;9(8):1225–9. https://doi.org/10.1021/TX9601566.

    Article  CAS  PubMed  Google Scholar 

  104. Miura M, Ohkubo T. Identification of human cytochrome P450 enzymes involved in the major metabolic pathway of fluvoxamine. Xenobiotica. 2007;37(2):169–79. https://doi.org/10.1080/00498250600718464.

    Article  CAS  PubMed  Google Scholar 

  105. Whomsley R, Strolin Benedetti M, Espie P, Usuki E, Wolff A, Baltes E. The conversion of hydroxyzine to cetirizine is mediated by alcohol dehydrogenase. Drug Metab Rev. 2005;37(Suppl. 2):390–1.

    Google Scholar 

  106. Wermuth CG. Analogues as a means of discovering new drugs. In: Fischer J, Ganellin CR, editors. Analogue-based drug discovery Weinheim. Germany: Wiley-VCH Verlag GmbH & Co. KGaA; 2006. p. 3–23.

    Google Scholar 

  107. Simons FER, Simons KJ. H1 antihistamines: current status and future directions. World Allergy Organ J. 2008;1(9):145–55.

    PubMed  PubMed Central  Google Scholar 

  108. Obradovic T, Dobson GG, Shingaki T, Kungu T, Hidalgo IJ. Assessment of the first and second generation antihistamines brain penetration and role of P-glycoprotein. Pharm Res. 2007;24(2):318–27. https://doi.org/10.1007/s11095-006-9149-4.

    Article  CAS  PubMed  Google Scholar 

  109. Markham A, Elkinson S. Luseogliflozin: first global approval. Drugs. 2014;74(8):945–50. https://doi.org/10.1007/s40265-014-0230-8.

    Article  CAS  PubMed  Google Scholar 

  110. Sasaki T, Seino Y, Fukatsu A, Sakai S, Samukawa Y. Safety, pharmacokinetics, and pharmacodynamics of single and multiple Luseogliflozin dosing in healthy Japanese males: a randomized, single-blind, Placebo-Controlled Trial. Adv Ther. 2014;31(3):345–61. https://doi.org/10.1007/s12325-014-0102-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Miyata A, Hasegawa M, Hachiuma K, Mori H, Horiuchi N, Mizuno-Yasuhira A, et al. Metabolite profiling and enzyme reaction phenotyping of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, in humans. Xenobiotica. 2017;47(4):332–45. https://doi.org/10.1080/00498254.2016.1193263.

    Article  CAS  PubMed  Google Scholar 

  112. Seino Y. Luseogliflozin for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2014;15(18):2741–9.

    CAS  PubMed  Google Scholar 

  113. Samukawa Y, Sata M, Furihata K, Ito T, Ueda N, Ochiai H, et al. Luseogliflozin, an SGLT2 inhibitor, in Japanese patients with mild/moderate hepatic impairment: a pharmacokinetic study. Clin Pharmacol Drug Dev. 2017;6(5):439–47. https://doi.org/10.1002/cpdd.364.

    Article  CAS  PubMed  Google Scholar 

  114. Webster R, Didier E, Harris P, Siegel N, Stadler J, Tilbury L, et al. PEGylated proteins: evaluation of their safety in the absence of definitive metabolism studies. Drug Metab Dispos. 2007;35(1):9–16. https://doi.org/10.1124/dmd.106.012419.

    Article  CAS  PubMed  Google Scholar 

  115. Herold DA, Keil K, Bruns DE. Oxidation of polyethylene glycols by alcohol dehydrogenase. Biochem Pharmacol. 1989;38(1):73–6. https://doi.org/10.1016/0006-2952(89)90151-2.

    Article  CAS  PubMed  Google Scholar 

  116. Veronese FM, Pasut G. PEGylation, successful approach to drug delivery. Drug Discov Today. 2005;10(21):1451–8. https://doi.org/10.1016/S1359-6446(05)03575-0.

    Article  CAS  PubMed  Google Scholar 

  117. Roy AB, Curtis CG, Powell GM. The metabolic sulphation of polyethyleneglycols by isolated perfused rat and guinea-pig livers. Xenobiotica. 1987;17(6):725–32.

    CAS  PubMed  Google Scholar 

  118. Roy AB, Curtis CG, Powell GM. The inhibition by chlorate of the sulphation of polyethyleneglycol in the isolated perfused guinea pig liver. Xenobiotica. 1988;18(9):1049–55.

    CAS  PubMed  Google Scholar 

  119. Nishiya Y, Nakai D, Urasaki Y, Takakusa H, Ohsuki S, Iwano Y, et al. Stereoselective hydroxylation by CYP2C19 and oxidation by ADH4 in the in vitro metabolism of tivantinib. Xenobiotica. 2016;46(11):967–76. https://doi.org/10.3109/00498254.2016.1144896.

    Article  CAS  PubMed  Google Scholar 

  120. Murai T, Takakusa H, Nakai D, Kamiyama E, Taira T, Kimura T, et al. Metabolism and disposition of [(14)C]tivantinib after oral administration to humans, dogs and rats. Xenobiotica. 2014;44(11):996–1008.

    CAS  PubMed  Google Scholar 

  121. Lee S-L, Shih H-T, Chi Y-C, Li Y-P, Yin S-J. Oxidation of methanol, ethylene glycol, and isopropanol with human alcohol dehydrogenases and the inhibition by ethanol and 4-methylpyrazole. Chem Biol Interact. 2011;191(1–3):26–31. https://doi.org/10.1016/j.cbi.2010.12.005.

    Article  CAS  PubMed  Google Scholar 

  122. Newbould BB. The future of drug discovery. In: Walker BC, Walker SR, editors. Trends and changes in drug discovery and development. Hingham: Kluwer Academic Publishers; 1988. p. 109.

    Google Scholar 

  123. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol. 1998;45(6):525–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Thomas RC, Ikeda GJ. The metabolic fate of tolbutamide in man and in the rat. J Med Chem. 1966;9(4):507–10. https://doi.org/10.1021/jm00322a014.

    Article  CAS  PubMed  Google Scholar 

  125. Lai C-L, Li Y-P, Liu C-M, Hsieh H-S, Yin S-J. Inhibition of human alcohol and aldehyde dehydrogenases by cimetidine and assessment of its effects on ethanol metabolism. Chem Biol Interact. 2013;202(1–3):275–82. https://doi.org/10.1016/j.cbi.2012.11.016.

    Article  CAS  PubMed  Google Scholar 

  126. Schindler JF, Berst KB, Plapp BV. Inhibition of human alcohol dehydrogenases by Formamides. J Med Chem. 1998;41(10):1696–701. https://doi.org/10.1021/JM9707380.

    Article  CAS  PubMed  Google Scholar 

  127. Hellgren M, Carlsson J, Oestberg LJ, Staab CA, Persson B, Hoeoeg J-O. Enrichment of ligands with molecular dockings and subsequent characterization for human alcohol dehydrogenase 3. Cell Mol Life Sci. 2010;67(17):3005–15. https://doi.org/10.1007/s00018-010-0370-2.

    Article  CAS  PubMed  Google Scholar 

  128. Staab CA, Hellgren M, Grafstroem RC, Hoeoeg J-O. Medium-chain fatty acids and glutathione derivatives as inhibitors of S-nitrosoglutathione reduction mediated by alcohol dehydrogenase 3. Chem Biol Interact. 2009;180(1):113–8. https://doi.org/10.1016/j.cbi.2009.01.008.

    Article  CAS  PubMed  Google Scholar 

  129. Xie PT, Hurley TD. Methionine-141 directly influences the binding of 4-methylpyrazole in human σσ alcohol dehydrogenase. Protein Sci. 1999;8(12):2639–44. https://doi.org/10.1110/ps.8.12.2639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zacny J, Zamakhshary M, Sketris I, Van Zanten SV. Systematic review: the efficacy of intermittent and on-demand therapy with histamine H2-receptor antagonists or proton pump inhibitors for gastro-oesophageal reflux disease patients. Aliment Pharmacol Ther. 2005;21(11):1299–312. https://doi.org/10.1111/j.1365-2036.2005.02490.x.

    Article  CAS  PubMed  Google Scholar 

  131. Stone CL, Hurley TD, Peggs CF, Kedishvili NY, Davis GJ, Thomasson HR, et al. Cimetidine inhibition of human gastric and liver alcohol dehydrogenase Isoenzymes: identification of inhibitor complexes by kinetics and molecular modeling. Biochemistry. 1995;34(12):4008–14. https://doi.org/10.1021/bi00012a019.

    Article  CAS  PubMed  Google Scholar 

  132. Battiston L, Tulissi P, Moretti M, Pozzato G. Lansoprazole and ethanol metabolism: comparison with omeprazole and cimetidine. Pharmacol Toxicol (Copenhagen). 1997;81(6):247–52.

    CAS  Google Scholar 

  133. Pozzato G, Franzin F, Moretti M, Lachin T, Benedetti G, Sablich R, et al. Effects of omeprazole on ethanol metabolism: an in vitro and in vivo rat and human study. Pharmacol Res. 1994;29(1):47–58. https://doi.org/10.1016/1043-6618(94)80097-9.

    Article  CAS  PubMed  Google Scholar 

  134. Lenz D, Juebner M, Bender K, Wintermeyer A, Beike J, Rothschild MA, et al. Inhibition of 1,4-butanediol metabolism in human liver in vitro. Naunyn Schmiedeberg's Arch Pharmacol. 2011;383(6):647–54. https://doi.org/10.1007/s00210-011-0627-9.

    Article  CAS  Google Scholar 

  135. Ramaswamy S, Scholze M, Plapp BV. Binding of Formamides to liver alcohol dehydrogenase. Biochemistry. 1997;36(12):3522–7. https://doi.org/10.1021/BI962491Z.

    Article  CAS  PubMed  Google Scholar 

  136. Venkataramaiah TH, Plapp BV. Formamides mimic aldehydes and inhibit liver alcohol dehydrogenases and ethanol metabolism. J Biol Chem. 2003;278(38):36699–706. https://doi.org/10.1074/jbc.M305419200.

    Article  CAS  PubMed  Google Scholar 

  137. Langhi C, Pedraz-Cuesta E, Haro D, Marrero PF, Rodriguez JC. Regulation of human class I alcohol dehydrogenases by bile acids. J Lipid Res. 2013;54(9):2475–84. https://doi.org/10.1194/jlr.M039404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Potter JJ, Cheneval D, Dang CV, Resar LMS, Mezey E, Yang VW. The upstream stimulatory factor binds to and activates the promoter of the rat class I alcohol dehydrogenase gene. J Biol Chem. 1991;266(23):15457–63.

    CAS  PubMed  Google Scholar 

  139. Stewart MJ, McBride MS, Winter LA, Duester G. Promoters for the human alcohol dehydrogenase genes ADH1, ADH2, and ADH3: interaction of CCAAT/enhancer-binding protein with elements flanking the ADH2 TATA box. Gene. 1990;90(2):271–9. https://doi.org/10.1016/0378-1119(90)90190-3.

    Article  CAS  PubMed  Google Scholar 

  140. Edenberg HJ. Regulation of the mammalian alcohol dehydrogenase genes. Prog Nucleic Acid Res Mol Biol. 2000;64:295–341.

    CAS  PubMed  Google Scholar 

  141. Van Ooij C, Snyder RC, Paeper BW, Duester G. Temporal expression of the human alcohol dehydrogenase gene family during liver development correlates with differential promoter activation by hepatocyte nuclear factor 1, CCAAT/enhancer-binding protein α, liver activator protein, and D-element-binding protein. Mol Cell Biol. 1992;12(7):3023–31. https://doi.org/10.1128/MCB.12.7.3023.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Jiang Y, Zhang T, Kusumanchi P, Han S, Yang Z, Liangpunsakul S, et al. Alcohol metabolizing enzymes, microsomal ethanol oxidizing system, cytochrome P450 2E1, catalase, and aldehyde dehydrogenase in alcohol-associated liver disease. Biomedicines. 2020;8(3).

  143. Su J-S, Tsai T-F, Chang H-M, Chao K-M, Su T-S, Tsai S-F. Distant HNF1 site as a master control for the human class I alcohol dehydrogenase gene expression. J Biol Chem. 2006;281(29):19809–21. https://doi.org/10.1074/jbc.M603638200.

    Article  CAS  PubMed  Google Scholar 

  144. Di L. Reaction phenotyping to assess victim drug-drug interaction risks. Expert Opin Drug Discovery. 2017;12(11):1105–15. https://doi.org/10.1080/17460441.2017.1367280.

    Article  CAS  Google Scholar 

  145. Stromberg P, Svensson S, Hedberg JJ, Nordling E, Hoog JO. Identification and characterisation of two allelic forms of human alcohol dehydrogenase 2. Cell Mol Life Sci. 2002;59(3):552–9.

    CAS  PubMed  Google Scholar 

  146. Buecher T, Brauser B, Conze A, Klein F, Langguth O, Sies H. State of oxidation-reduction and state of binding in the cytosolic NADH-system as disclosed by equilibration with extracellular lactate-pyruvate in hemoglobin-free perfused rat liver. Eur J Biochem. 1972;27(2):301–17. https://doi.org/10.1111/j.1432-1033.1972.tb01840.x.

    Article  CAS  Google Scholar 

  147. Zorzano A, Herrera E. Differences in kinetic characteristics and in sensitivity to inhibitors between human and rat liver alcohol dehydrogenase and aldehyde dehydrogenase. Gen Pharmacol. 1990;21(5):697–702. https://doi.org/10.1016/0306-3623(90)91020-R.

    Article  CAS  PubMed  Google Scholar 

  148. Palacharla VRC, Chunduru P, Ajjala DR, Bhyrapuneni G, Nirogi R, Li AP. Development and validation of a higher-throughput cytochrome P450 inhibition assay with the novel cofactor-supplemented permeabilized cryopreserved human hepatocytes (MetMax human hepatocytes). Drug Metab Dispos. 2019;47(10):1032–9. https://doi.org/10.1124/dmd.119.088237.

    Article  CAS  PubMed  Google Scholar 

  149. Nirogi R, Palacharla RC, Uthukam V, Manoharan A, Srikakolapu SR, Kalaikadhiban I, et al. Chemical inhibitors of CYP450 enzymes in liver microsomes: combining selectivity and unbound fractions to guide selection of appropriate concentration in phenotyping assays. Xenobiotica. 2015;45(2):95–106. https://doi.org/10.3109/00498254.2014.945196.

    Article  CAS  PubMed  Google Scholar 

  150. Draper AJ, Madan A, Parkinson A. Inhibition of coumarin 7-hydroxylase activity in human liver microsomes. Arch Biochem Biophys. 1997;341(1):47–61. https://doi.org/10.1006/abbi.1997.9964.

    Article  CAS  PubMed  Google Scholar 

  151. Moody GC, Griffin SJ, Mather AN, McGinnity DF, Riley RJ. Fully automated analysis of activities catalysed by the major human liver cytochrome P450 (CYP) enzymes: assessment of human CYP inhibition potential. Xenobiotica. 1999;29(1):53–75.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors greatly appreciate the help of Mr. John C. Murch in editing the manuscript.

Author information

Authors and Affiliations

  1. Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, CT, 06340, USA

    Li Di, Amanda Balesano & Samantha Jordan

  2. Department of Chemistry, Stanford University, Stanford, CA, 94305, USA

    Sophia M. Shi

Authors
  1. Li Di
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amanda Balesano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samantha Jordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sophia M. Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Di.

Additional information

Guest Editors: Diane Burgess, Marilyn Morris and Meena Subramanyam

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 300 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Di, L., Balesano, A., Jordan, S. et al. The Role of Alcohol Dehydrogenase in Drug Metabolism: Beyond Ethanol Oxidation. AAPS J 23, 20 (2021). https://doi.org/10.1208/s12248-020-00536-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12248-020-00536-y

Keywords

Search

Navigation