Sulfotransferase (SULT) enzymes catalyze the sulfate conjugation of drugs, other xenobiotics, neurotransmitters and hormones. The genes for SULT1A1 and SULT1A2 contain common genetic polymorphisms that are associated with individual variations in levels of enzyme activity as well as variations in biochemical and physical properties. We set out to compare the frequencies of common SULT1A1 and SULT1A2 alleles in Caucasian, Chinese and African-American subjects. Allele frequencies for SULT1A1*1, *2 and *3 in 242 Caucasian subjects were 0.656, 0.332 and 0.012, respectively. Frequencies of those same alleles were significantly different in 290 Chinese subjects: 0.914, 0.080 and 0.006, respectively, as were frequencies in 70 African-American subjects: 0.477, 0.294 and 0.229, respectively. Ethnic variation in allele frequencies was also observed for SULT1A2, with frequencies in Caucasian subjects for SULT1A2*1, *2 and *3 of 0.507, 0.389 and 0.104; frequencies in Chinese of 0.924 and 0.076 with no *3 alleles observed; and, finally, in African-Americans frequencies of 0.637, 0.249 and 0.114, respectively. We also found that SULT1A1*2 and SULT1A2*2, the most common variant alleles for these two genes, were in positive linkage disequilibrium in all three populations studied, with D' values of 0.776 in Caucasian (P < 0.001), 0.915 in Chinese (P < 0.001) and 0.864 in African-American subjects (P < 0.001). These observations represent a step towards determining the possible functional implications for individual variations in sulfate conjugation of common genetic polymorphisms for SULT1A1 and SULT1A2.
Ligand-mediated activation of the pregnane X receptor (PXR, NR1I2) is postulated to affect both hepatic and intestinal gene expression, because of the presence of this nuclear receptor in these important drug metabolizing organs; as such, activation of this receptor may elicit the coordinated regulation of PXR target genes in both tissues. Induction of hepatic and intestinal drug metabolism can contribute to the increased metabolism of drugs, and can result in adverse or undesirable drug-drugis a potent activator of the rat PXR and was characterized for its effects on hepatic and intestinal gene expression in female Sprague-Dawley rats by DNA microarray analysis. Transcriptional profiling in liver and small intestine revealed that L-742694 and dexamethasone (DEX) induced the prototypical battery of PXR target genes in liver, including CYP3A, Oatp2, and UGT1A1. In addition, both DEX and L-742694 induced common gene expression profiles that were specific to liver or small intestine, but there was a distinct lack of coordinated gene expression of genes common to both tissues. This pattern of gene regulation occurred in liver and small intestine independent of PXR, constitutive androstane receptor, or hepatic nuclear factor-4␣ expression, suggesting that other factors are involved in controlling the extent of coordinated gene expression in response to a PXR agonist. Overall, these results suggest that ligand-mediated activation of PXR and induction of hepatic, rather than small intestinal, drug metabolism genes would contribute to the increased metabolism of orally administered pharmaceuticals.
In human hepatocytes, both fenofibric acid and clofibric acid are inducers of CYP3A4 and CYP2C8. Gemfibrozil is also an inducer of CYP3A4, but acts as both an inducer and an inhibitor of CYP2C8. In this system, all fibrates are weak inducers of UGT1A1. The enzyme inducing effects of fibrates appear to be mediated via a mechanism(s) other than PXR activation. These results suggest that fibrates may have potential to cause various pharmacokinetic drug interactions via their differential effects on enzyme induction and/or inhibition.
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