Genetic polymorphisms of CYP2C8 and CYP2C9 in Chinese type 2 diabetes mellitus

Abstract

Abstract: AIM: To identify the frequencies and distributive characteristics of CYP2C8 and CYP2C9 in Chinese type 2 diabete mellitus. METHODS: The functional allele CYP2C8^＊3, CYP2C8P404A,CYP2C9^＊ 3 were detected by PCR-RFLP and DHPLC methods in 222 T2DM patients.The CYP2C8IVS 2 (-5insert t)whose function remains unclear was also detected.The frequency of all these alleles were calculated. RESULTS: The alleles of CYP2C8^＊3 and P404A were not found in 222 T2DM patients.The allelic frequency of CYP2C8IVS2 (-5insert t)and CYP2C9^＊3 were 43 % and 2.48 %, respectively.There was no significant difference between the male and female on CYP2C8 IVS2 (-5insert t)and CYP2C9^＊3 alleles. The allelic frequency of CYP2C8IVS2 (-5insert t) combined with CYP2C9^＊1^＊3 was 6.3 %.There was no significant difference between the male and female on it, too. CONCLUSION: The frequency of CYP2C9^＊3 was 2.48 % in Chinese T2DM patients. The alleles of CYP2C8^＊3 and P404 were not found. The incidence of CYP2C8IVS2 (-5insert t)mutant was 43.0 %, and whether it has influences on CYP2C8 metabolism activity needs further study.

Key words: CYP2C8, type 2 diabetes mellitus, genetic polymorphism, PCR-RFLP, DHPLC

CLC Number:

R587.1

HE Jun, ZHOU Wei, WANG Lian-ci, HE Ting-ye, WANG Dan, FAN Lan, ZHANG Wei, ZHOU Hong-hao. Genetic polymorphisms of CYP2C8 and CYP2C9 in Chinese type 2 diabetes mellitus[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2009, 14(3): 300-306.

References

[1] 肖洲生, 王连生, 朱冰, 等.细胞色素P450 酶系[M] 周宏灏.遗传药理学.北京:科学技术出版社, 2001:87.
[2] Sandberg M, Johansson I, ChristensenM, et al.The impact of CYP2C9 genetics and oral contraceptives on cytochrome P450 2C9 phenotype[J].Drug Metab Dispos, 2004, 32(5):484-489.
[3] Garcí a-Martí n E, Martí nez C, Ladero JM, et al.Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals [J].Mol Diagn Ther, 2006, 10(1):29-40.
[4] Dai D, Zeldin DC, Blaisdell JA, et al.Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid[J].Pharmacogenet-ics, 2001, 11(7):597-607.
[5] Bahadur N, Leathart JB, Mutch E, et al.CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6α-hydroxylase activity in human liver microsomes [J].Biochem Pharmacol, 2002, 64(11):1579-1589.
[6] Nakajima M, Fujiki Y, Noda K, et al.Genetic polymorphisms of CYP2C8 in Japanese population[J].Drug Metab Dispos, 2003, 31(6):687-690.
[7] Soyama A, Saito Y, Hanioka N, et al.Non-synonymous single nucleotide alterations found in the CYP2C8 gene result in reduced in vitro paclitaxel metabolism[J].Biol Pharm Bull, 2001, 24(12):1427-1430.
[8] NiemiM, Leathart JB, NeuvonenM, et al.Polymorphism in CYP2C8 is associated with reduced plasma concentrations of repaglinide[J].Clin Pharmacol Ther, 2003, 74(4):380-387.
[9] McGarry JD, Dobbins RL.Fatty acids, lipotoxicity, and insulin secretion[J].Diabetologia, 1999, 42(2):128-138.
[10] McGarry JD.Bnating lecture 2001 dy sregulation of fatty acid metabolism in the etiology of type 2 diabetes[J].Diabetes, 2002, 51(1):7-18.
[11] Santbrook J, Fritsch EF, Maniatis T.Molecular Cloning: A Laboratory Manual[M].2nd ed.Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 1989:16-19.
[12] Fisslthaler B, Popp R, Kiss L, et al.Cytochrome P450 2C is an EDHF synthase in coronary arteries[J].Nature, 1999, 401(6752):493-497.
[13] Takahashi H,Wilkinson GR, Caraco Y, et al.Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients[J]. Clin Pharmacol Ther, 2003, 73(3):253-263.
[14] Xie HG, Prasad HC, Kim RB, et al.CYP2C9 allelic variants:ethnic distribution and functional significance [J].Adv Drug Deliv Rev, 2002, 54(10):1257-1270.
[15] Yu BN, Luo CH, Wang D, et al.CYP2C9 allele variants in Chinese hypertension patients and healthy controls[J]. Clin Chim Acta, 2004, 348(1 2):57-61.
[16] Luo CH, Wang A, Zhu RH, et al.Gender specific association of CYP2C9＊3 with hyperlipidaemia in Chinese[J]. Br J Clin Pharmacol, 2005, 60(6):629-631.