Modulation of cytochrome P450 1A (CYP1A) enzymes by monomethylmonothioarsonic acid (MMMTAV) in vivo and in vitro

Arsenic is a naturally occurring element that poses a major health threat to millions of people around the globe [1]. Arsenic-contaminated drinking water is always portrayed as the greatest menace to human health because of harboring the notorious inorganic forms (iAs); arsenite (iAsIII) and arsenate (iAsV). However, decades of investigations have revealed that these inorganic forms undergo progressive biotic transformation, specifically methylation, yielding a complex network of organoarsenicals (oAs), some of which are as toxic or, sometimes, more reactive than their inorganic precursors [2].

Both trivalent and pentavalent methylated oAs have been detected in mammals upon iAs exposure and are presumably produced through a series of reactions, the definitive sequence of which is yet to be elucidated. One of the proposed reaction sequences is the Hayakawa's pathway which suggests non-enzymatic formation of trivalent arsenic-glutathione complexes, followed by sequential methylation [3]. Interestingly, a group of sulfur-containing metabolites, in which pentavalent methylated oAs undergo further thiolation, has been lately identified. With the absence of a conclusive evidence, thioarsenicals are possibly derived from trivalent arsenic-glutathione complexes via microbial gut metabolism [2,4].

Thiolated arsenicals, including monomethylmonothioarsonic acid (MMMTAV), dimethylmonothioarsinic acid (DMMTAV), and dimethyldithioarsinic acid (DMDTAV), have been reported in humans orally exposed to contaminated drinking water [5,6] or intravenously receiving arsenic trioxide (ATOIII)-based treatment for acute promyelocytic leukemia (APL) [7,8]. Additionally, thioarsenicals have been also detected in blood [9] and urine of different laboratory animals [10] in response to oral iAsIII exposure.

Cytochromes P450 (CYPs) are a superfamily of hemoproteins that catalyze the oxidation of both endobiotics and xenobiotics. CYP1A1 and CYP1A2 are the members of CYP1A subfamily which are prominent contributors to the metabolism of endogenous compounds, thus serving physiological functions. Therefore, alterations in their activity can entail homeostatic derangements, leading ultimately to a disease state [11]. CYP1A1 and CYP1A2 are also involved in the metabolism of various hepatically cleared drugs [[12], [13], [14], [15]].

In this regard, their activity may decrease efficacy and/or toxicity of a drug by metabolizing its active form. In another scenario, such activity can enhance efficacy or toxicity of the drug by activating its inert prodrug [16] or producing toxic metabolites [17], respectively. Consequently, drug interactions may evolve as a result of a perpetrator drug modulating the way CYP1A1/2 act on a victim drug [18].

Xenobiotic metabolism by CYP1A enzymes extends to include environmental toxicants. In this regard, these enzymes are considered as a double-edged sword that can either potentiate or alleviate the deleterious outcome of such foreign chemicals. CYP1A enzymes are infamously known for the bioactivation of procarcinogens such as the polycyclic aromatic hydrocarbons (PAHs; e.g. 3-methylcholanthrene (3-MC) and benzo(a)pyrene (B[a]P)) [13,[19], [20], [21], [22]]. These compounds trigger their own metabolism because they are also the archetypes of CYP1A enzymes induction, a process mediated by activating their master regulator, the aryl hydrocarbon receptor (AHR), along with its regulatory module, the xenobiotic response element (XRE) [3].

Over the last few decades, our laboratory and others have established a connection between the exposure to different heavy metals [23], including arsenicals [3,24], and the varying constitutive expression of the AHR-regulated enzymes such as CYP1A1 and CYP1A2. Arsenic-based compounds have been also reported to affect the inducible expression of these enzymes upon co-exposure to their toxic inducers, a realistic situation that can be attributed to the environmental ubiquity of both arsenicals and AHR-activating pollutants [3].

In this study we hypothesized that MMMTAV can modulate the AHR signaling pathway with subsequent modification of CYP1A1 and CYP1A2 expressions. The objectives of this study were to evaluate the possible effects of MMMTAV on both inducible, using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a potent AHR agonist, and basal expressions of both CYP1A1 and CYP1A2 enzymes, and to elucidate the driving mechanism of such effects.

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