RT Journal Article
SR Electronic
T1 Isomer- and sex-specific bioactivation of mononitrotoluenes. Role of enterohepatic circulation.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 651
OP 657
VO 13
IS 6
A1 J P Chism
A1 D E Rickert
YR 1985
UL http://dmd.aspetjournals.org/content/13/6/651.abstract
AB 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)