CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6alpha-hydroxylase activity in human liver microsomes.

Published cDNA sequences suggest the existence of non-synonymous single nucleotide polymorphisms in the cytochrome P450 CYP2C8. To determine whether these polymorphisms could be confirmed in a Caucasian population and to investigate whether additional polymorphisms occur in the coding and upstream regions of this gene, we screened for previously described and for novel polymorphisms using PCR-RFLP and SSCP analysis. We confirmed the existence of two of the previously detected polymorphisms which give rise to the amino acid substitutions I264M and K399R, respectively, but failed to detect three others in our population. We also confirmed that a recently identified polymorphism (R139K) is linked to K399R (CYP2C8*3) in our study population. The allele frequencies for the I264M (CYP2C8*4 allele) and the CYP2C8*3 allele were 0.075 and 0.15, respectively. Three novel polymorphisms (T-370G, C-271A and T1196C/L390S) were also detected with the upstream polymorphisms showing allele frequencies of 0.061 and 0.196, respectively, but the L390S polymorphism detected only in a single subject. An additional single subject was heterozygous for a polymorphism recently described in African-Americans (A805T; CYP2C8*2 allele). The functional significance of the two upstream polymorphisms and the CYP2C8*3 and CYP2C8*4 alleles was investigated in human liver microsomes. Samples heterozygous for CYP2C8*3 showed significantly lower paclitaxel 6alpha-hydroxylase activity compared with wild-type samples. Median activity associated with CYP2C8*4 also appeared lower than the wild-type but the difference was not significant. There was no evidence that either upstream polymorphism gave rise to altered CYP2C8 expression.

Survey of atherosclerotic disease in Asian subjects with cardiovascular disease risk factors who were not receiving lipid-lowering agents.

BACKGROUND: Carotid intima media thickness (CIMT) is a surrogate marker for atherosclerosis, used to identify asymptomatic individuals at increased risk of cardiovascular events. The primary objective of this study was to obtain the distribution of CIMT measurements in Asian individuals with cardiovascular disease (CVD) risk factors who were not receiving lipid-lowering agents. METHODS: Mean CIMT based on ultrasonographic measurement of 12 sites within the common carotid artery was recorded for 2726 subjects across eight Asian countries who had two or more CVD risk factors but were not receiving lipid-lowering therapy. CVD risk factors and lipid and glucose profiles were analyzed with respect to distribution of CIMT and high-sensitivity C-reactive protein (hs-CRP) values. RESULTS: The overall mean (SD) of mean CIMT (mean-mean CIMT) was 0.662 (0.16) mm. There was a significant variation in mean-mean CIMT across countries (P<0.0001). Mean-mean CIMT values (mm) by age were: 0.485, 0.527, 0.614, 0.665, 0.715 and 0.797 for ≤ 29, 30-39, 40-49, 50-59, 60-69 and ≥ 70 years, respectively. Multivariate analyses confirmed a significant association between increasing mean-mean CIMT and increasing age, male gender, low high-density lipoprotein-cholesterol (HDL-C) levels and elevated fasting blood glucose levels. Analysis of log-transformed hs-CRP levels showed significant association with increasing waist circumference, low-density lipoprotein-cholesterol, body-mass index, high blood glucose levels and low HDL-C. CONCLUSIONS: Our data show normative mean-mean CIMT data for Asian subjects with two or more CVD risk factors who are not receiving lipid-lowering therapy, which may guide CVD risk-stratification of asymptomatic individuals in Asia.