Arsenic is a naturally occurring hazardous element that is environmentally ubiquitous in various chemical forms. Upon exposure, the human body initiates an elimination pathway of progressive methylation into relatively less bioreactive and more easily excretable pentavalent methylated forms. Given its association with decreasing the internal burden of arsenic with ensuing attenuation of its related toxicities, biomethylation has been applauded for decades as a pure route of arsenic detoxification. However, the emergence of detectable trivalent species with profound toxicity has opened a long-standing debate regarding whether arsenic methylation is a detoxifying or bioactivating mechanism. In this review, we approach the topic of arsenic metabolism from both perspectives to create a complete picture of its potential role in the mitigation or aggravation of various arsenic-related pathologies. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
The cytochrome P450 1 A (CYP1A) subfamily enzymes are involved in the metabolic activation of several xenobiotics to toxic metabolites and reactive intermediates, resulting ultimately in carcinogenesis. Mercury and halogenated aromatic hydrocarbons (HAHs), typified by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD), are persistent environmental pollutants involved in the modulation of aryl hydrocarbon receptor (AHR) gene battery, including cytochrome P450 (CYP) genes. We previously investigated the effect of coexposure to either inorganic or organic mercury (Hg+2 and MeHg) with TCDD on CYP1A1 in vitro. Thus, we examined the impact of coexposure to Hg+2 or MeHg and TCDD on AHR‐regulated genes (Cyp1a1/1a2) in vivo and in vitro. Therefore, male C57BL/6 mice were injected intraperitoneally with MeHg or Hg+2 (2.5 mg/kg) in the absence and presence of TCDD (15 μg/kg) for 6 or 24 h. The concentration‐dependent effect of MeHg was examined in murine hepatoma Hepa1c1c7 cells. In vivo, both MeHg and Hg2+ inhibited the TCDD‐mediated induction of Cyp1a1/1a2 mRNA levels. However, Only Hg2+ was able to inhibit the TCDD‐mediated induction at posttranscriptional levels of CYP1A1/1A2 protein and catalytic activity, suggesting differential modulation effects by Hg+2 and MeHg. In addition, the inhibitory role of HO‐1 (Heme oxygenase‐1) on CYP1A activity induced by TCDD was investigated using a HO‐1 competitive inhibitor, tin‐mesoporphyrin, that partially restored the MeHg‐mediated decrease in CYP1A1 activity. This study demonstrates that MeHg, alongside Hg2+, can differentially modulate the TCDD‐induced AHR‐regulated genes (Cyp1a1/1a2) at different expression levels in C57BL/6 mice liver and Hepa1c1c7 cells.
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