Isomer- and sex-specific bioactivation of mononitrotoluenes. Role of enterohepatic circulation

Abstract

2-Nitrotoluene (2NT) induces DNA repair in the in vivo-in vitro hepatocyte unscheduled DNA synthesis assay in male, but not female, Fischer-344 rats. 3-Nitrotoluene (3NT) and 4-nitrotoluene (4NT) are inactive in both sexes. The structurally related rat hepatocarcinogen, 2,6-dinitrotoluene, which also displays a sex-specific toxicity, requires biliary excretion for bioactivation. Therefore, the role of enterohepatic circulation in the development of the isomer- and sex-specific hepatic bioactivation of the mononitrotoluenes was studied in male and female Fischer-344 rats. Male rats excreted 28.6, 10.8, and 9.8% of a dose (200 mg/kg) of 2NT, 3NT, or 4NT, respectively, in the bile 12 hr after the dose. Female rats excreted 9.6, 4.3, and 1.3% of a dose of 2NT, 3NT, or 4NT, respectively, in the bile 12 hr after the dose. Of the 2NT-related material excreted in the bile, 77% in males (22.0% of the dose) and 86% in females (8.3% of the dose) was 2-nitrobenzyl glucuronide. Of the 3NT-related material excreted in the bile, 28% in males (2.8% of the dose) and 16% in females (0.7% of the dose) was 3-nitrobenzyl glucuronide. Of the 4NT-related material excreted in bile, 9% in males (0.9% of the dose) and 7% in females (0.1% of the dose) was 4-nitrobenzyl glucuronide. Inhibition of enterohepatic circulation by bile duct cannulation resulted in a decrease in hepatic macromolecular covalent binding by 98, 75, and 78% in male rats, and by 85, 44, and 45% in female rats after 2NT, 3NT, or 4NT, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)