Effect of in Vivo Chromate, Acetone and Combined Treatment on Rat Liver in Vitro Microsomal Chromium(VI) Reductive Activity and on Cytochrome P450 Expression

Abstract

Cytochrome P450 (P450IIE1) in rat has previously been shown to exhibit high chromate [Cr(VI)] reductase activity (Mikalsen et al. 1991). The present study reports on the effect of chromate treatment in vivo in rats and on the modulating effect of acetone+fasting on chromium(VI) toxicity. No effect of intraperitoneal injection with 5 mg chromate/kg was observed, whereas 15 mg chromate/kg decreased the liver microsomal Cr(VI) reductase activity by about 30% in in vitro microsomal incubations. In addition, the P450 and cytochrome b5 contents were decreased by about 30% and 25% respectively. Acetone+fasting caused increases of total microsomal P450 and cytochrome b5 contents, associated with similar increases in apoproteins P450IIE1 and P450IIB1+2, and their corresponding mRNA, and apoprotein NADPH‐P450 reductase, as well as NADPH‐P450 reductase and microsomal Cr(VI) reductive activities. Related to acetone+fasting alone, when given in combination with chromate (15 mg/kg) the Cr(VI) reductive activity was decreased by about 30%, associated with decreases in the P450 and cytochrome b5 contents, 65% and 35% respectively. This further reduced the apoprotein levels of P450IIB1+2, P450IIE1, and NADPH‐P450 reductase to 90%, 60%, and 40%, respectively, and the mRNA levels of P450IIB2 and P450IIE1. No effect was observed on NADPH‐P450 reductase activity. This dose also caused some macroscopic alterations in the liver. In contrast, the P450IIE1 apoprotein level in the lung was apparently stabilized or even increased by chromate in rats treated with acetone+fasting. The results show that acetone+fasting causes induction of microsomal Cr(V) metabolism and increases chromium toxicity. Chromate does not induce its own metabolism in liver and interferes, probably in a complex way, with P450 enzymes and their gene expression, especially when induced.