SY18-1 * ETHNIC DIFFERENCES OF DISULFIRAM PHARMACOGENETIC EFFECT IN ASIAN POPULATION

Abstract

Introduction. The development of alcoholism results from multiple risk factors involving complex gene-gene and gene-environment interactions. Alcohol sensitivity is a well-known trait marker predisposing toward alcoholism via regulating the reinforcing and certain intoxicating effects of ethanol. The compound promoting acute ethanol intoxicating effect could contribute to the alcoholism treatment. The ethnic variations of aldehyde dehydrogenase (ALDH), the principal enzyme for acetaldehyde elimination in alcohol metabolism, will provide an opportunity to clarify the pharmacogenetic effect of disulfiram for the Asian population. Method. In preclinical animal studies, the male C57BL/6J mice were adapted to assess the effect of disulfiram on ethanol sensitivity by using a battery of three behavioral assays: Rotarod for ethanol-induced ataxia, hypothermia and sedation. Clinically, we recruited alcoholic patients with ALDH2\*1/\*1 and ALDH2\*1/\*2 genotypes identified by PCR-RFLP and confirmed by direct nucleotide sequencing. Before and after disulfiram treatment in one-week interval, the participants received an oral dose of ethanol (0.2 g/kg). The blood ethanol and acetaldehyde, cardiovascular hemodynamic parameters were measured following ethanol ingestion. Result. The disulfiram increased ethanol-induced hypothermia and sedation in C57BL/6J mice.In human study, no acetaldehyde accumulation in ALDH2\*1/\*1 alcoholic subjects and mild elevation (∼40 uM) in ALDH2\*1/\*2 alcoholics following low dose ethanol ingestion. After the disulfiram treatment, there were significantly higher levels of blood acetaldehyde (peak concentration ∼200 uM in ALDH2\*1/\*1 group and ∼500 uM in ALDH2\*1/\*2 group). Consistently, the cardiovascular hemodynamic parameters showed marked alterations (∼50% increase of heart rate) after disulfiram treatment. Conclusion. The disulfiram-alcohol reaction is sufficiently potent to make alcoholics stop alcohol drinking, but should reduce treatment dose for subjects with variant ALDH2*2 and be aware of the potential hazard consequences for uncontrollable alcohol drinking in the treatment course.