Variation in AKR1C3, which encodes the neuroactive steroid synthetic enzyme 3α-HSD type 2 (17β-HSD type 5), moderates the subjective effects of alcohol.
BACKGROUND
Animal models suggest that neuroactive steroids contribute to alcohol's acute effects. We previously reported that a common nonsynonymous polymorphism, AKR1C3 2 in the gene encoding the enzyme 3α-HSD2/17β-HSD5, and a synonymous single nucleotide polymorphism (SNP), rs248793, in SRD5A1, which encodes 5α-reductase, were associated with alcohol dependence (AD).


OBJECTIVE
The aim of the study was to investigate whether these polymorphisms moderate subjective effects of alcohol in humans and whether AKR1C3 2 affects neuroactive steroid synthesis.


METHODS
Sixty-five Caucasian men (34 lighter and 31 heavier drinkers; mean age 26.2 years) participated in a double-blind laboratory study where they consumed drinks containing no ethanol or 0.8 g/kg of ethanol. Breath alcohol, heart rate (HR), and self-reported alcohol effects were measured at 40-min intervals, and genotype was examined as a moderator of alcohol's effects. Levels of the neuroactive steroid 5α-androstane-3α,17β-diol and its precursors, 3α,5α-androsterone and dihydrotestosterone, were measured at study entry using GC/MS.


RESULTS
Initially, carriers of the AD-protective AKR1C3 2 G allele had higher levels of 5α-androstane-3α,17β-diol relative to the precursor 3α,5α-androsterone than C allele homozygotes. AKR1C3 2 G allele carriers exhibited greater increases in heart rate and stimulant and sedative effects of alcohol than C allele homozygotes. The genotype effects on sedation were observed only in heavier drinkers. The only effect of the SRD5A1 SNP was to moderate HR. There were no interactive effects of the two SNPs.


CONCLUSIONS
The observed effects of variation in a gene encoding a neuroactive steroid biosynthetic enzyme on the rate of 17β-reduction of androsterone relative to androstanediol and on alcohol's sedative effects may help to explain the association of AKR1C3 2 with AD.
Alcohol Research Center, Department of Psychiatry, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT, 06030-1410, USA.
Verica
V
Milivojevic
Richard
R
Feinn
Henry R
HR
Kranzler
Jonathan
J
Covault
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000428:Alcohol Drinking / Q000235:genetics* / Q000523:psychology*; D000437:Alcoholism / Q000235:genetics / Q000523:psychology; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000738:Androsterone / Q000494:pharmacology; D001378:Azasteroids / Q000494:pharmacology / Q000627:therapeutic use; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004311:Double-Blind Method; D000068538:Dutasteride; D000431:Ethanol / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology; D014644:Genetic Variation; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011963:Receptors, GABA-A / Q000187:drug effects; D055815:Young Adult
D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D002492:Central Nervous System Depressants; D018757:GABA Modulators; D011963:Receptors, GABA-A; D000431:Ethanol; D000738:Androsterone; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000068538:Dutasteride