ADH1B

ADH1B Full Name

alcohol dehydrogenase 1B (class I), beta polypeptide

ADH1B Introduction

ADH1B (alcohol dehydrogenase 1B, class I beta polypeptide) is a member of the alcohol dehydrogenase family of enzymes that catalyze the oxidation of alcohols to aldehydes. The gene encoding ADH1B is located on human chromosome 4q23, within a cluster of seven ADH genes spanning approximately 370 kb. ADH1B produces a protein of approximately 375 amino acids that functions as a homodimer or heterodimer with other class I ADH subunits (ADH1A and ADH1C). This enzyme is best known for its critical role in the metabolism of ethanol, converting ethanol to acetaldehyde as the first and rate-limiting step in alcohol metabolism. ADH1B is predominantly expressed in the liver, where it accounts for a significant portion of total alcohol dehydrogenase activity, but it is also found in the stomach, kidney, and other tissues. Genetic polymorphisms in ADH1B have profound effects on alcohol metabolism and are strongly associated with protection against alcohol dependence and alcohol-related diseases.

Figure 1. Strcuture of ADH1B.

Enzymatic Function and Role in Alcohol Metabolism
ADH1B is the primary enzyme responsible for the oxidation of ethanol to acetaldehyde in the liver, a critical first step in ethanol metabolism. After ethanol consumption, ADH1B converts ethanol to acetaldehyde, which is subsequently oxidized to acetate by aldehyde dehydrogenase (ALDH2). The rate of ethanol metabolism is largely determined by ADH activity, and ADH1B is the most active form among the class I ADH enzymes. The enzyme exhibits Michaelis-Menten kinetics with a relatively high Km for ethanol (approximately 1 mM), meaning it becomes saturated only at high ethanol concentrations. This is why alcohol metabolism follows zero-order kinetics at intoxicating blood alcohol levels. In addition to ethanol, ADH1B also metabolizes other alcohols, including methanol, ethylene glycol, and various steroid and retinoid substrates, contributing to the clearance of these compounds from the body.

Clinical Significance: Protection Against Alcohol Dependence
The functional variants of ADH1B have profound effects on alcohol drinking behavior and the risk of developing alcohol use disorder (AUD). Individuals carrying the ADH1B2 or ADH1B3 alleles have a significantly reduced risk of alcohol dependence compared to individuals homozygous for the ADH1B1 allele. The protective effect is most pronounced in East Asian populations, where the ADH1B2 allele is common. The mechanism of protection involves the rapid accumulation of acetaldehyde after ethanol consumption, leading to aversive symptoms including facial flushing, nausea, tachycardia, and headache, a response similar to that caused by disulfiram (Antabuse). This aversive reaction discourages heavy drinking and reduces the likelihood of developing dependence. Meta-analyses have consistently demonstrated that the ADH1B*2 allele is associated with a two- to three-fold reduction in the risk of alcohol dependence. Interestingly, the protective effect is independent of ALDH2 genotype, although the combination of ADH1B*2 with the inactive ALDH2*2 allele produces the strongest aversive response and the greatest protection.

Alternate Names for ADH1B

ADH1B; alcohol dehydrogenase 1B (class I), beta polypeptide; ADH2; alcohol dehydrogenase 1B; ADH, beta subunit; aldehyde reductase; alcohol dehydrogenase subunit beta; alcohol dehydrogenase 2 (class I), beta polypeptide;