Gene polymorphism of CYP2C subfamily and inter-individual differences in drug metabolism

对154名日本受试者进行了CYP2C18和CYP2C19突变等位基因的重合性研究。突变后的等位基因分别为：CYP2C18m1(T204A)和CYP2C18mFR(A-460T)，CYP2C19为CYP2C19m1(G689A)和CYP2C19m2(G636A)。结果表明，CYP2C18m1和CYP2C18mFR分别与CYP2C19m2和CYP2C19m1的基因型完全一致。这一发现表明，本研究中检测到的CYP2C18和CYP2C19突变之间存在非常密切的联系，至少在日本人群中是这样。我们还研究了在酵母细胞中表达的野生型(CYP2C9-Ile359)和突变型(CYP2C9-Leu359)在7种代谢反应中的动力学。对于所研究的所有底物的代谢，Leu变异体的Vmax/Km值比野生型小。野生型和亮氨酸变异株的Vmax/Km相差3.4~26.9倍。结果表明，Ile359Leu的变化降低了CYP2C9介导的反应的催化活性，尽管不同底物的活性下降的程度不同。

The coincidence of mutant alleles of CYP2C18 and CYP2C19 was studied in 154 Japanese subjects. The mutant alleles of CYP2C18 were CYP2C18m1(T204A) and CYP2C18mFR(A-460T) and those of CYP2C19 were CYP2C19m1(G689A) and CYP2C19m2(G636A). The results indicated that genotypes of CYP2C18m1 and CYP2C18mFR are completely coincident with those of CYP2C19m2 and CYP2C19m1, respectively. The finding suggests that the mutations of CYP2C18 and CYP2C19 examined in the present study are very closely linked with each other at least in a Japanese population. We also studied the kinetics of seven metabolic reactions using wild-type (CYP2C9-Ile359) and mutant (CYP2C9-Leu359) of CYP2C9 expressed in yeast cells. For the metabolism of all the substrates studied, The Leu variant exhibited smaller Vmax/Km values than wild-type. The differences in Vmax/Km between wild-type and Leu variant varied from 3.4-fold to 26.9-fold. The result suggests that Ile359Leu changes decreases the catalytic activity of CYP2C9-mediated reactions although the extent of decrease in the activity varies between substrates.