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

CYP2C亚家族基因多态性及药物代谢个体差异

• 批准号: 10672145
• 负责人: CHIBA Kan
• 金额: $ 2.37万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10672145/
• 关键词: CYP2C9; CYP2C18; CYP2C19; Polymorphism; inter-individual differences; linkage

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.

研究了154名日本人CYP2C18和CYP2C19突变等位基因的重合性。CYP2C18的突变等位基因为CYP2C18m1（T204A）和CYP2C18mFR(A-460T)， CYP2C19的突变等位基因为CYP2C19m1（G689A）和CYP2C19m2（G636A）。结果表明，CYP2C18m1和CYP2C18mFR基因型分别与CYP2C19m2和CYP2C19m1基因型完全一致。这一发现表明，在本研究中检测的CYP2C18和CYP2C19突变至少在日本人群中彼此密切相关。我们还研究了酵母细胞中表达的CYP2C9野生型（CYP2C9- ile359）和突变型（CYP2C9- leu359）的7种代谢反应的动力学。对于所研究的所有底物的代谢，Leu变体的Vmax/Km值比野生型小。野生型与Leu变异的Vmax/Km差异在3.4 ~ 26.9倍之间。结果表明，Ile359Leu的改变降低了cyp2c9介导反应的催化活性，但活性降低的程度因底物而异。

项目成果

Kubota T,Hibi N,Chiba K: "Linkage of mutant alleles of CYP2C18 and CYP2C19 in a Japanese population"Biochem Pharmacol. 55. 2039-2042 (1998)

Kubota T、Hibi N、Chiba K：“日本人群中 CYP2C18 和 CYP2C19 突变等位基因的连锁”Biochem Pharmacol。

Takanashi K, Tainaka H, Kobayashi K, Yasumori T, Hosokawa M, Chiba K: "CYP2CIle359 and Leu359 variants: enzyme kinetics study seven substrates"Pharmacogenetics. 10. 95-104 (2000)

Takanashi K、Tainaka H、Kobayashi K、Yasumori T、Hosokawa M、Chiba K：“CYP2CIle359 和 Leu359 变体：酶动力学研究七种底物”药物遗传学。

Takanashi K, Taninaka H, Kobayashi K, Yasumori T, Hosokawa M, Chiba K: "CYP2C9Ile359 and Leu359 variants : enzyme kinetics study seven substrates."Pharmacogenetics. 10. 95-104 (2000)

Takanashi K、Taninaka H、Kobayashi K、Yasumori T、Hosokawa M、Chiba K：“CYP2C9Ile359 和 Leu359 变体：酶动力学研究七种底物。”药物遗传学。

Kubota, T, HIBI N, Chiba K: "Linkage of mutant alleles of CYP2C18 and CYP2C19 in a Japanese population"Biochem Pharmacol. 55. 2039-2042 (1998)

Kubota, T, HIBI N, Chiba K：“日本人群中 CYP2C18 和 CYP2C19 突变等位基因的连锁”Biochem Pharmacol。

Takanashi K,Tainaka H,Kobayashi K,Yasumori T,Hosokawa M,Chiba K: "CYP2C9Ile359 and Leu359 variants : enzyme kinetics study seven substrates"Pharmacogenetics. 10. 95-104 (2000)

Takanashi K、Tainaka H、Kobayashi K、Yasumori T、Hosokawa M、Chiba K：“CYP2C9Ile359 和 Leu359 变体：酶动力学研究七种底物”药物遗传学。