20 The ALDH2 SNP Glu487Lys, designated as ALDH2*2, was monomorphic in the population study (Table 4). This SNP is common in Asian subjects21 but is extremely rare in white individuals (http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=671). Finally, two CYP2E1

variant alleles designated as CYP2E1*2 and CYP2E1*5 were analyzed. The variant allele CYP2E1*2, which consists of a nucleotide change G1132A, causes the www.selleckchem.com/products/gsk1120212-jtp-74057.html amino acid substitution Arg76His, and is associated with impaired activity,22 was monomorphic in the study population (Table 4), whereas the CYP2E1*5 allele, which contains silent mutations and is associated with increased activity, was polymorphic, with allele frequencies similar to those described for white subjects.23 No sex-related differences were observed Pirfenidone in the frequencies for any of the polymorphisms identified in the study. With the exception of the ADH1C SNPs 272 and 350, which were strongly linked (P < 0.001), no linkage was observed between the polymorphisms studied, and no significant departures from Hardy Weinberg's equilibrium were observed for any of the SNPs studied. Table 5 summarizes the distribution of pharmacokinetic parameters stratified by polymorphisms of ethanol-metabolizing enzymes. No differences in any of the parameters were identified regarding the

ADH1B Arg48His polymorphism. Subjects carrying ADH1B Ser60 showed lower metabolic rates as compared with nonmutated control subjects (P = 0.012,

t test). However, the difference in metabolic rates between genotypes does not appear to correlate with other parameters such as Tmax, Cmax, and AUC (Table 5). Thus, the physiological importance of ADH1B Ser60 is uncertain. The most striking differences in ethanol pharmacokinetics are related to the ADH1C polymorphisms (Table 5). Carriers of the ADH1C 78X, ADH1C 272Gln, or ADH1C 350Phe alleles display lower rates of ethanol metabolism as compared with noncarriers of the respective polymorphisms (P < 0.001 for all comparisons that remain significant after Bonferroni's correction), thus indicating that the ADH1C polymorphisms identified MCE公司 in this study are relevant to the rate of ethanol metabolism. In contrast, no differences in any of the pharmacokinetic parameters analyzed were observed with regard to CYP2E1 polymorphisms (Table 5). Multiple comparison analyses for all pharmacokinetic parameters were carried out, including the relevant polymorphisms, that is, ADH1B Thr60, ADH1C 78X, ADH1C 272Gln, and ADH1C 350Phe. Backward logistic regression indicates that none of these polymorphisms was related to Tmax or Cmax. The polymorphism ADH1C 350Phe was related to increased AUC (P = 0.01), and the polymorphisms ADH1C 78X and ADH1C 350Phe were related to decreased ethanol metabolic rate (P < 0.001 for both SNPs, with or without correction for sex).