Dimethylmonothioarsinic acid (DMMTAV) differentially modulates the expression of AHR-regulated cytochrome P450 1A enzymes in vivo and in vitro

Abstract

Dimethylmonothioarsinic acid (DMMTAV), a pentavalent thio-arsenic derivative, has been found in bodily fluids and tissues including urine, liver, kidney homogenates, plasma, and red blood cells. Although DMMTAV is a minor metabolite in humans and animals, its substantial toxicity raises concerns about potential carcinogenic effects. This toxicity could be attributed to arsenicals' ability to regulate cytochrome P450 1 A (CYP1A) enzymes, pivotal in procarcinogen activation or detoxification. The current study investigates DMMTAV's impact on CYP1A1/2 expression, individually and in conjunction with its inducer, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). C57BL/6 mice were intraperitoneally injected with 6 mg/kg DMMTAV, alone or with 15 μg/kg TCDD, for 6 and 24 h. Similarly, Hepa-1c1c7 cells were exposed to DMMTAV (0.5, 1, and 2 μM) with or without 1 nM TCDD for 6 and 24 h. DMMTAV hindered TCDD-induced elevation of Cyp1a1 mRNA, both in vivo (at 6 h) and in vitro, associated with reduced CYP1A regulatory element activation. Interestingly, in C57BL/6 mice, DMMTAV boosted TCDD-induced CYP1A1/2 protein and activity, unlike Hepa-1c1c7 cells where it suppressed both. DMMTAV co-exposure increased TCDD-induced Cyp1a2 mRNA. While Cyp1a1 mRNA stability remained unchanged, DMMTAV negatively affected protein stability, indicated by shortened half-life. Baseline levels of CYP1A1/2 mRNA, protein, and catalytic activities showed no significant alterations in DMMTAV-treated C57BL/6 mice and Hepa-1c1c7 cells. Taken together, these findings indicate, for the first time, that DMMTAV differentially modulates the TCDD-mediated induction of AHR-regulated enzymes in both liver of C57BL/6 mice and murine Hepa-1c1c7 cells suggesting that thio-arsenic pentavalent metabolites are extremely reactive and could play a role in the toxicity of arsenic.