LUNG-CANCER RISK IN RELATION TO THE CYP2C9-ASTERISK-1 CYP2C9-ASTERISK-2 GENETIC-POLYMORPHISM AMONG AFRICAN-AMERICANS AND CAUCASIANS IN LOS-ANGELES-COUNTY, CALIFORNIA/

CYP2C9 is involved in the metabolism of warfarin and a wide array of o ther therapeutic agents. It also appears to play a role, along with ot her cytochrome P450 enzymes, in the metabolism of benzo[a]pyrene, a ca rcinogen in tobacco smoke, A relatively common allelic variant (termed R144C, Cys(144) Or more recently CYP2C92) has been described that re sults in the substitution of cysteine for arginine at residue 144 and appears to reduce enzyme activity. We therefore examined the possible association between the presence of the CYP2C92 variant allele and ri sk of lung cancer using peripheral blood DNA from 329 incident cases o f lung cancer (152 African-American and 177 Caucasian) and 700 (239 Af rican-American and 461 Caucasian) population controls in Los Angeles C ounty, California, Among the population controls the frequency of the CYP2C92 variant allele was lower (p = 0.00002) among African-American s (0.036) than among Caucasians (0.100). The presence of the CYP2C92 variant allele was not associated with a decreased risk of lung cancer ; slight but nonstatistically significant elevations in risk were obse rved for both African-Americans [odds ratio (OR) 1.22, 95% confidence interval (CI) 0.48-3.11] and Caucasians (OR = 1.55, 95% CI 0.96-2.48), The ORs were slightly and nonsignificantly elevated for all histologi c types without substantive variation. The association also did not va ry materially according to smoking history or whether subjects had the homozygous deletion of the GSTM1 gene, We found no support for the hy pothesis that the CYP2C92 variant allele decreases the risk of lung c ancer, The role of P450s, including CYP2C9, in benzo[a]pyrene metaboli sm is not fully defined, and CYP2C9 catalyses detoxication as well as activation steps, Thus it is not inconceivable that diminished CYP2C9 activity could increase metabolic activation of benzo[cr]pyrene to car cinogenic intermediates. Nonetheless, the small increased risk associa ted the CYP2C92 variant allcle in our data is consistent with chance and should not be overinterpreted.