London S J, Daly A K, Leathart J B, Navidi W C, Idle J R
Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles 90033, USA.
Pharmacogenetics. 1996 Dec;6(6):527-33. doi: 10.1097/00008571-199612000-00006.
CYP2C9 is involved in the metabolism of warfarin and a wide array of other therapeutic agents. It also appears to play a role, along with other cytochrome P450 enzymes, in the metabolism of benzo[a]pyrene, a carcinogen in tobacco smoke. A relatively common allelic variant (termed R144C, Cys144 or more recently CYP2C92) has been described that results 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 risk of lung cancer using peripheral blood DNA from 329 incident cases of lung cancer (152 African-American and 177 Caucasian) and 700 (239 African-American and 461 Caucasian) population controls in Los Angeles County, California. Among the population controls the frequency of the CYP2C92 variant allele was lower (p = 0.00002) among African-Americans (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 observed 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 histologic types without substantive variation. The association also did not vary materially according to smoking history or whether subjects had the homozygous deletion of the GSTM1 gene. We found no support for the hypothesis that the CYP2C92 variant allele decreases the risk of lung cancer. The role of P450s, including CYP2C9, in benzo[a]pyrene metabolism 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[a]pyrene to carcinogenic intermediates. Nonetheless, the small increased risk associated the CYP2C92 variant allele in our data is consistent with chance and should not be overinterpreted.
细胞色素P450 2C9（CYP2C9）参与华法林及众多其他治疗药物的代谢。它似乎还与其他细胞色素P450酶一起，参与烟草烟雾中的致癌物苯并[a]芘的代谢。已发现一种相对常见的等位基因变体（称为R144C、Cys144或最近的CYP2C92），该变体导致第144位残基上的精氨酸被半胱氨酸取代，似乎会降低酶活性。因此，我们使用来自加利福尼亚州洛杉矶县329例肺癌新发病例（152例非裔美国人、177例白种人）和700例（239例非裔美国人、461例白种人）人群对照的外周血DNA，研究了CYP2C92变体等位基因的存在与肺癌风险之间的可能关联。在人群对照中，非裔美国人（0.036）的CYP2C92变体等位基因频率低于白种人（0.100）（p = 0.00002）。CYP2C92变体等位基因的存在与肺癌风险降低无关；非裔美国人[比值比（OR）1.22，95%置信区间（CI）0.48 - 3.11]和白种人（OR = 1.55，95% CI 0.96 - 2.48）的风险均有轻微但无统计学意义的升高。所有组织学类型的OR值均有轻微且无统计学意义的升高，无实质性差异。该关联也未因吸烟史或受试者是否存在谷胱甘肽S-转移酶M1（GSTM1）基因的纯合缺失而有实质性变化。我们没有找到支持CYP2C92变体等位基因降低肺癌风险这一假设的证据。包括CYP2C9在内的细胞色素P450在苯并[a]芘代谢中的作用尚未完全明确，并且CYP2C9催化解毒以及活化步骤。因此，CYP2C9活性降低可能会增加苯并[a]芘向致癌中间体的代谢活化，这并非不可思议。尽管如此，我们数据中与CYP2C92变体等位基因相关的小幅风险增加可能是偶然的，不应过度解读。
