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

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  • Theme: Celebrating Women in the Pharmaceutical Sciences
  • Published:
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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.

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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

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  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

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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

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