Mixed Function Oxidase Enzyme Responses to in Vivo and in Vitro Chromate Treatment

Abstract

Chromium (Cr) is an essential nutrient in humans which aids in the metabolism of cholesterol, glucose and fats. The trivalent state (Cr(III)) is essential in trace doses, while Cr(VI) is toxic to mammals in acute and subchronic doses [Langard and Norseth, 1986] and long term exposure has been associated with respiratory cancer [Chiazze and Wolf, 1980; Langard and Norseth, 1975; Mancuso, 1975]. Unusually high rates of lung cancer have been reported in workers in chrome plating, leather tanning, and other Cr related industries [Chiazze and Wolf, 1980; Langard and Norseth, 1975; Mancuso, 1975]. The mechanisms for the toxic and genotoxic effects of Cr are only partially understood. The differences in toxicity of the two most common oxidation states, Cr(VI) and Cr(III), are due to the relative lack of ability of cationic Cr(III) compounds to cross cell membranes, while Cr(VI) as the chromate anion, crosses biological membranes freely [Aaseth et al., 1982; Wiegand et al., 1985]. The intracellular reduction of Cr(VI) has recently been shown to result in both Cr(V) and Cr(III) production, both of which are putative DNA damaging agents [Goodgame et al., 1982; Jennette, 1982]. Compounds such as glutathione (GSH) [Aaseth et al., 1982; Connett and Wetterhahn, 1983], ascorbate [Connett and Wetterhahn, 1983], and hydrogen peroxide [Cupo and Wetterhahn, 1985] participate in the intracellular reduction of Cr(VI). Reduction takes place both in mitochondria [Alexander et al., 1982], and the endoplasmic reticulum [Gruber and Jennette, 1978]. When GSH is the reductant a toxic glutathionyl radical (GS) may be formed [Wetterhahn, 1990, in press]. Cr(III) binds to nucleophiles including some sulfhydryl (SH) containing enzymes, with some resulting enzyme inhibition. Thus the metabolism of Cr(VI) is important for the interaction of Cr with DNA [Tsapakos and Wetterhahn, 1983], with GSH [Wiegand et al., 1985] and with SH groups on other cellular macromolecules. Previous studies with microsomes have indicated that cytochrome P-450 (P-450), an SH containing enzyme, acts as an electron donor in the microsomal reduction of Cr(VI) [Gruber and Jennette, 1978].