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The detoxification of quinones through NAD(P)H:quinone oxidoreductase (NQO1) is a crucial mechanism to maintain cellular homeostasis. The exposure to heavy metals, specifically methylmercury (MeHg), induces several antioxidant enzymes, including NQO1. The nuclear factor erythroid 2-related factor-2 (NRF2) is known to regulate the expression of Nqo1 gene and also the aryl hydrocarbon receptor (AHR) is another Nqo1 gene regulator. This co-regulation prompted us to investigate which transcription factor (NRF2 or AHR) orchestrates the regulation of NQO1 expression upon MeHg exposure. Therefore, we investigated how MeHg can modulate the level of NQO1 expression by exposing Hepa-1c1c7 cells to several concentrations of MeHg with and without the addition of NQO1 inducers, DL-sulforaphane (SUL) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We found that the mRNA expression of Nqo1 is up-regulated by MeHg in time- as well as dose-dependent fashions. Additionally, MeHg increased the NQO1 at all expression levels with and without the presence of its inducers, SUL or TCDD. Furthermore, the MeHg-mediated increase of NQO1 expression was in parallel with a concurrent increase in the nuclear localization of NRF2 protein, but not that of AHR. Mechanistically, the antioxidant response element-driven reporter gene activity was induced by 215% upon MeHg exposure. Also, transfecting Hepa-1c1c7 with Nrf2 siRNA reduced the MeHg-induced NQO1 protein expression by 60%. In conclusion, our findings provide evidence supporting the hypothesis that MeHg upregulates the Nqo1 gene through a transcriptional mechanism at least in part via a NRF2-dependent mechanism., Competing Interests: 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., (© 2023 The Author(s).)

Arsenic trioxide (ATO) is a highly toxic arsenical which has been successfully exploited for treating acute promyelocytic leukemia (APL). Unfortunately, its therapeutic efficacy is accompanied by serious toxicities with undeciphered mechanisms. Cytochrome P450 1A (CYP1A) enzymes undergo modulation by arsenicals, with ensuing critical consequences regarding drug clearance or procarcinogen activation. Here, we investigated the potential of ATO to alter basal and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1/1A2 expressions. Mouse-derived hepatoma Hepa-1c1c7 cells were exposed to 0.63, 1.25, and 2.5 μM ATO with or without 1 nM TCDD. ATO increased TCDD-induced CYP1A1/1A2 mRNA, protein, and activity. Constitutively, ATO induced Cyp1a1/1a2 transcripts and CYP1A2 protein. ATO increased AHR nuclear accumulation and subsequently increased XRE-luciferase reporter activity. ATO enhanced CYP1A1 mRNA and protein stabilities. In conclusion, ATO up-regulates CYP1A in Hepa-1c1c7 cells transcriptionally, post-transcriptionally, and post-translationally. Therefore, ATO can be implicated in clearance-related interactions with CYP1A1/1A2 substrates, or in excessive activation of environmental procarcinogens., 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 © 2023 Elsevier B.V. All rights reserved.)

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 (MMMTA V ) 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 MMMTA V , with or without 15 μg/kg TCDD for 6 and 24 h. Moreover, murine Hepa-1c1c7 and human HepG2 cells were treated with MMMTA V (1, 5, and 10 μM), with or without 1 nM TCDD for 6 and 24 h. MMMTA V 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, MMMTA V significantly increased TCDD-induced CYP1A1 protein and activity in C57BL/6 mice and Hepa-1c1c7 cells, while both were significantly inhibited by MMMTA V treatment in HepG2 cells. CYP1A2 mRNA, protein and activity induced by TCDD were significantly increased by MMMTA V co-exposure. MMMTA V 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 MMMTA V -treated Hepa-1c1c7 cells. Our findings show that MMMTA V 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., 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 © 2023 Elsevier B.V. All rights reserved.)

Arsenic trioxide (ATO) has evolved from an environmental threat to a successful therapy for acute promyelocytic leukemia (APL) and probably for solid tumors in the future. However, its efficacy comes at a cost of multi-organ toxicity whose mechanism remains unresolved. Arsenicals have been reported to modulate cytochrome P450 1A (CYP1A) enzymes, thus modifying activation/detoxification of drugs/procarcinogens. Therefore, this study aimed to investigate the possible effects of ATO on CYP1A1 and CYP1A2, in absence and presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using in vivo and in vitro models. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO with or without 15 μg/kg TCDD for 6 and 24 h. Furthermore, HepG2 cells were treated with ATO (1, 5, and 10 μM) with or without 1 nM TCDD for 6 and 24 h. ATO significantly inhibited TCDD-mediated induction of CYP1A1/1A2 mRNA, protein, and activity in both models. ATO differentially modulated CYP1A1/1A2 basal levels in vivo. We also demonstrated that ATO downregulates CYP1A through inhibiting the transcriptional activation of its regulatory element at both basal and inducible levels. Additionally, ATO significantly induced mRNA and protein of heme oxygenase 1 (HMOX1) in vivo and in vitro. In HepG2 cells, inhibition of HMOX1 by tin (IV) mesoporphyrin (IX) (SnMP) resulted in a partial restoration of the TCDD-mediated induction of CYP1A1 activity that was inhibited by ATO co-exposure. Our findings show that ATO alters both constitutive and inducible CYP1A1/1A2 expressions through transcriptional and HMOX1-mediated post-translational mechanisms. This implies the possible involvement of ATO in clearance-related consequences for the substrates of these enzymes such as drug-drug interactions or suboptimal toxicant elimination., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Arsenic is well-recognized as one of the most hazardous elements which is characterized by its omnipresence throughout the environment in various chemical forms. From the simple inorganic arsenite (iAs III ) and arsenate (iAs V ) molecules, a multitude of more complex organic species are biologically produced through a process of metabolic transformation with biomethylation being the core of this process. Because of their differential toxicity, speciation of arsenic-based compounds is necessary for assessing health risks posed by exposure to individual species or co-exposure to several species. In this regard, exposure assessment is another pivotal factor that includes identification of the potential sources as well as routes of exposure. Identification of arsenic impact on different physiological organ systems, through understanding its behavior in the human body that leads to homeostatic derangements, is the key for developing strategies to mitigate its toxicity. Metabolic machinery is one of the sophisticated body systems targeted by arsenic. The prominent role of cytochrome P450 enzymes (CYPs) in the metabolism of both endobiotics and xenobiotics necessitates paying a great deal of attention to the possible effects of arsenic compounds on this superfamily of enzymes. Here we highlight the toxicologically relevant arsenic species with a detailed description of the different environmental sources as well as the possible routes of human exposure to these species. We also summarize the reported findings of experimental investigations evaluating the influence of various arsenicals on different members of CYP superfamily using human-based models., (Copyright © 2021 El-Ghiaty et al.)