Modulation of cytochrome P450 1A (CYP1A) enzymes by monomethylmonothioarsonic acid (MMMTAV) in vivo and in vitro

Inorganic arsenic (iAs) is a natural toxicant which, upon entering the biosphere, undergoes extensive biotransformation and becomes a portal for generating various organic intermediates/products. The chemical diversity of iAs-derived organoarsenicals (oAs) is accompanied by varying degree of toxicity that can be held responsible, at least partly, for the overall health outcome of the originally encountered parent inorganic molecule. Such toxicity may originate from arsenicals ability to modulate cytochrome P450 1A (CYP1A) enzymes, whose activity is critical in activating/detoxifying procarcinogens. In this study, we evaluated the effect of monomethylmonothioarsonic acid (MMMTAV) on CYP1A1 and CYP1A2 in absence and presence of their inducer; 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Therefore, C57BL/6 mice were intraperitoneally injected with 12.5 mg/kg MMMTAV, with or without 15 mu g/kg TCDD for 6 and 24 h. Moreover, murine Hepa-1c1c7 and human HepG2 cells were treated with MMMTAV (1, 5, and 10 mu M), with or without 1 nM TCDD for 6 and 24 h. MMMTAV significantly inhibited TCDD-mediated induction of CYP1A1 mRNA, both in vivo and in vitro. This effect was attributed to decreased transcriptional activation of CYP1A regulatory element. Interestingly, MMMTAV significantly increased TCDD-induced CYP1A1 protein and activity in C57BL/6 mice and Hepa-1c1c7 cells, while both were significantly inhibited by MMMTAV treatment in HepG2 cells. CYP1A2 mRNA, protein and activity induced by TCDD were significantly increased by MMMTAV co-exposure. MMMTAV had no effect on CYP1A1 mRNA stability or protein stability and did not alter their half-lives. At basal level, only CYP1A1 mRNA was significantly decreased in MMMTAV-treated Hepa-1c1c7 cells. Our findings show that MMMTAV exposure potentiates procarcinogen-induced catalytic activity of both CYP1A1 and CYP1A2 in vivo. This effect entails excessive activation of such procarcinogens upon co-exposure, with potentially negative health-related outcomes.

Automated summary

Inorganic arsenic (iAs) undergoes biotransformation and generates various organic intermediates/products in the biosphere, which are accompanied by varying degrees of toxicity. This study evaluates the effect of monomethylmonothioarsonic acid (MMMTAV) on CYP1A1 and CYP1A2 enzymes, which play a critical role in activating/detoxifying procarcinogens. MMMTAV inhibits the induction of CYP1A1 mRNA by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), decreases transcriptional activation of CYP1A regulatory element, and increases the protein and activity of CYP1A1 induced by TCDD. Additionally, MMMTAV co-exposure enhances the catalytic activity of both CYP1A1 and CYP1A2, potentially leading to negative health outcomes.