Interactions between CYP3A5*3 and POR*28 polymorphisms and lipid lowering response with atorvastatin.

Abstract

The polymorphic enzyme P450 oxidoreductase (POR) transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to cytochrome P450 (CYP)3A enzyme s, which metabolize atorvastatin. This suggests that variations in the CYP3A5 and POR genes may influence the response to statins. We aimed to investigate the association and interactions between CYP3A5*3 and POR*28 polymorphisms and the lipid-lowering effects of atorvastatin in a Chinese population. Genotypes were determined by polymerase chain reaction (PCR) with restriction fragment length polymorphism analysis and by PCR with direct sequencing analysis for 179 hyperlipidaemic patients treated with atorvastatin 20mg once daily for 4weeks. Serum levels of triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were determined before and after treatment. For the 179 patients (including 100 males), the variant allele frequencies of CYP3A5*3 and POR*28 were 73.75 and 41.62%, respectively. Among all patients, no significant association was found between CYP3A5*3 polymorphisms and TG, TC, LDL-C and HDL-C levels before and after treatment with 20mg of atorvastatin daily for 4weeks. Homozygotes for the POR*28 Tallele showed a significantly lower mean concentration of LDL-C than homozygotes for the POR*28 Callele (POR*28TT vs POR*28CC: 2.46±0.37 vs 2.69±0.49mmol/L, P=0.019) after treatment with atorvastatin 20mg daily for 4weeks. After adjustment for age, sex and body mass index, CYP3A5 non-expressors who were POR*28 wild-type homozygotes showed significantly higher mean TC and LDL-C levels than those who were POR*28 variant homozygotes, both at baseline (*3/CC vs *3/TT; TC: 7.30±0.73 vs 6.94±0.36mmol/L, P=0.026; LDL-C: 3.88±0.70 vs 3.47±0.46mmol/L, P=0.009) and after atorvastatin treatment (*3/CC vs *3/TT; TC: 6.03±0.64 vs 5.69±0.34mmol/L, P=0.017; LDL-C: 2.80±0.62 vs 2.43±0.40mmol/L, P=0.008). CYP3A5 non-expressors who were POR*28 wild-type homozygotes showed significantly higher TC and LDL-C levels at baseline (*3/CC vs *1/CC; TC: 7.30±0.73 vs 6.95±0.41mmol/L, P=0.010; LDL-C: 3.88±0.70 vs 3.55±0.39mmol/L, P=0.010) and showed higher TC levels after atorvastatin treatment (*3/CC vs *1/CC; 6.03±0.64 vs 5.73±0.27mmol/L, P=0.012), in comparison with patients expressing CYP3A5 who were POR*28 wild-type homozygotes. CYP3A5 non-expressors who were POR*28 heterozygotes showed significantly lower percentage changes in TC from baseline than those expressing CYP3A5 who were POR*28 heterozygotes (*3/CT vs *1/CT; 16.77±3.13 vs 18.40±4.16mmol/L, P=0.031). POR*28 is associated with a poorer response to atorvastatin, but there is no association of the latter with CYP3A5*3. POR*28 single nucleotide polymorphisms are associated with greater increases in the effect on plasma lipids in non-expressors of CYP3A5. Besides CYP3A5*3 genetic polymorphism, POR*28 genetic polymorphism might also be responsible for the marked interindividual variability in the lipid-lowering response to atorvastatin.