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

Dimethylmonothioarsinic acid (DMMTA ^V ), a pentavalent thio-arsenic derivative, has been found in bodily fluids and tissues including urine, liver, kidney homogenates, plasma, and red blood cells. Although DMMTA ^V 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 DMMTA ^V '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 DMMTA ^V , alone or with 15 μg/kg TCDD, for 6 and 24 h. Similarly, Hepa-1c1c7 cells were exposed to DMMTA ^V (0.5, 1, and 2 μM) with or without 1 nM TCDD for 6 and 24 h. DMMTA ^V 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, DMMTA ^V boosted TCDD-induced CYP1A1/2 protein and activity, unlike Hepa-1c1c7 cells where it suppressed both. DMMTA ^V co-exposure increased TCDD-induced Cyp1a2 mRNA. While Cyp1a1 mRNA stability remained unchanged, DMMTA ^V negatively affected protein stability, indicated by shortened half-life. Baseline levels of CYP1A1/2 mRNA, protein, and catalytic activities showed no significant alterations in DMMTA ^V -treated C57BL/6 mice and Hepa-1c1c7 cells. Taken together, these findings indicate, for the first time, that DMMTA ^V 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)