The Influence of Two CYP2C9 Promoter SNPs on CYP2C9 Expression and Caffeine’s Impact on CYP1A2
thesisposted on 21.02.2013, 00:00 by David J. Vaynshteyn
The R150H polymorphism—the most common in African Americans—is associated with decreased S-warfarin clearance and as a result lower warfarin dose requirements. CYP2C9 R150H was found to be in strong linkage disequilibrium with CYP2C9 promoter single nucleotide polymorphism (SNP) 1766T>C (r2=0.90) and always inherited with CYP2C9 promoter SNP -1188T>C. In liver tissues from African Americans carrying the CYP2C9*1/*8 genotype, CYP2C9*8 was associated with decreased allelic expression of CYP2C9 at mRNA levels. Results from a promoter assay showed the combination of promoters SNPs (-1766T>C and -1188T>C) leads to a decreased promoter activity of CYP2C9. The results suggest that promoter region SNPs linked to the CYP2C9 R150 polymorphism decrease CYP2C9 expression and may contribute to the CYP2C9*8 allele phenotype. Caffeine is the active substance in coffee and its’ continual consumption can lead to an attenuated response known as tolerance. Previously, results from rat studies have shown that caffeine is an inducer of CYP1A2, the enzyme responsible for caffeine metabolism. The possibility exists that caffeine tolerance could be due, in part, to the induction of CYP1A2. However, it is unknown if this phenomena occurs in humans. Our results from luciferase assays performed in HepG2 cells showed that caffeine is not an activator of aromatic hydrocarbon receptor (AhR), a transcription factor involved in CYP1A2 upregulation. Also, caffeine did not induce CYP1A2 in primary human hepatocytes. On the other hand, caffeine was able to induce CYP1A2 expression in rat hepatocytes as expected. Our results suggest that caffeine from ordinary coffee drinking does not induce CYP1A2 expression in humans and that factors other than CYP1A2 induction by caffeine contribute to the development of caffeine tolerance.