Dosimetry of chlorinated quinone metabolites of pentachlorophenol in the livers of rats and mice based upon measurement of protein adducts

The dosimetry of chlorinated quinones arising from metabolism of pentachlorophenol (PCP), in the livers of male Sprague-Dawley rats and B6C3F(1) mice was investigated via measurements of cysteinyl protein adducts and estimates of the second-order reaction rate constants between the quinones and the proteins. We had previously shown that adducts of tetrachloro-1,4-benzoquinone (Cl-4-1,4-BQ) and tetrachloro-1,2-benzosemiquinone (Cl-4-1,2-SQ) were observed at the highest levels in the livers of Sprague-Dawley rats to which PCP had been administered by gavage (5-40 mg/kg body wt) (Biomarkers 1, 232-243, 1996), In the current study we observed that adducts of Cl-4-1,4-BQ and tetrachloro-1,2-benzoquinone (Cl-4-1,2-BQ) were predominant in the livers of B6C3F(1) mice receiving 20 mg PCP/kg body wt. The second-order rate constants, representing in vitro reactions between Cl-4-1,2-BQ and Cl-4-1,4-BQ and various cysteine residues of hepatic proteins of liver cytosol and Liver nuclei, were estimated to be 0.012-1.96 L(g protein)(-1) hr(-1) in rats and 0.082-1.67 L(g protein)(-1) hr(-1) in mice. The estimated tissue doses of the quinones to liver cytosol decreased in the order rat Cl-4-1,4-BQ > mouse Cl-4-1,4-BQ > mouse Cl-4-1,2-BQ and to liver nuclei in the order mouse Cl-4-1,2-BQ > mouse Cl-4-1,4-BQ > rat Cl-4-1,4-BQ. The corresponding doses of Cl-4-1,2-SQ could not be inferred due to our inability to estimate the second-order rate constants. After aggregating the estimated contributions of all quinone species, mice had a fourfold greater dose to liver nuclei than rats, whereas rats had a threefold greater dose to liver cytosol. The increased nuclear dose to mouse liver compared to that of the rat suggests that the mouse is at greater risk to hepatic DNA damage from PCP-derived quinones. Investigation of the time course of levels of unconjugated tetrachlorohydroquinone (Cl(4)HQ) in the livers indicated that about 0.4% of Cl(4)HQ was oxidized to Cl-4-1,4-BQ in both rats and mice. (C) 1997 Academic Press.