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

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 1A (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 6mg/kg DMMTAV , alone or with 15μg/kg TCDD, for 6 and 24h. Similarly, Hepa-1c1c7 cells were exposed to DMMTAV (0.5, 1, and 2μM) with or without 1nM TCDD for 6 and 24h. DMMTAV hindered TCDD-induced elevation of Cyp1a1 mRNA, both in vivo (at 6h) 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 mouse and murine Hepa-1c1c7 cells suggesting that thio-arsenic pentavalent metabolites are extremely reactive and could play a role in the toxicity of arsenic.