Comparative analysis of human CYP3A4 and rat CYP3A1 induction and relevant gene expression by bisphenol A and diethylstilbestrol: Implications for toxicity testing paradigms

Environmental pollutants parathion, paraquat and bisphenol A show distinct effects towards nuclear receptors-mediated induction of xenobiotics-metabolizing cytochromes P450 in human hepatocytes

“…In the paper by Sui et al it was demonstrated species-specific ability of BPA to activate human but not mouse PXR (Sui et al, 2012) supporting the relevance of human based cellular models for environmental studies and deciphering molecular mechanism of their action. Recent studies demonstrated CYP3A4 mRNA and activity induction in human hepatoma DPX2 cells (with stably integrated hPXR) and human intestinal LS180 cells (Sui et al, 2012;Kuzbari et al, 2013). In our study, we confirm their finding at CYP3A4 mRNA as well as protein level by employing human hepatocytes ( Fig.…”

“…4H) in contrast to their observation of elevated CYP3A4 catalytic activity at 10 mM (Kuzbari et al, 2013). Possible explanation may involve either higher metabolic conversion of BPA in metabolically more competent cells of our system, human hepatocytes or just different sensitivities of used methods.…”

CYP3A4 mutation causes vitamin D–dependent rickets type 3

“…Enzymatic activity of both the WT and p.I301T mutant were inhibited by ketoconazole to levels indistinguishable from empty vector ( Figure 2D: 1.1 ± 0.1 vs. 1.0 ± 0.1, n = 4 for each, P = 0.39). In contrast to the results for 1,25-dihydroxyvitamin D 3 as a substrate, the p.I301T mutant had significantly decreased activity relative to the WT ( Figure 2D: 30.0 ± 1.6 vs. 50.1 ± 1.6, n = 4 for each, P < 0.001) for luciferin IPA (19). We identified a gain-of-function mutation in CYP3A4 in 2 unrelated children with severe rickets due to accelerated vitamin D metabolite inactivation.…”

“…Because the kidney cell line (HEK293T) does not express CYP3A4, we used it to create a cell-based assay. This assay directly measures the conversion of luciferin IPA to luciferin by CYP3A4 and is used to examine CYP3A4 induction (19). Enzymatic activity of both the WT and p.I301T mutant were inhibited by ketoconazole to levels indistinguishable from empty vector ( Figure 2D: 1.1 ± 0.1 vs. 1.0 ± 0.1, n = 4 for each, P = 0.39).…”

Association of Serum Bisphenol-A Concentration and Male Reproductive Function Among Exposed Workers

“…The possible health hazards of BPA ingestion have been mostly deduced from rat and mice studies. Several toxicological studies have reported adverse reproductive effects in animals exposed to BPA during the prenatal or perinatal period (Kuzbari et al 2013;Richter et al 2007). Exposure to BPA has adversely affected the reproduction of wildlife including annelids (both aquatic and terrestrial), mollusks, crustaceans, insects, fish, and amphibians, as well as embryonic development (Oehlmann et al 2009).…”