The metabolic fate of benzo [a] pyrene in vivo

Abstract

[³H]-B[a]P absorption, distribution, metabolism, excretion and macromolecular binding in male Sprague-Dawley rats were investigated following administration by intratracheal instillation through a cannula. [³H]- radioactivity in various organs was determined at timed intervals between 5 and 360 min. Elimination of radioactivity from lungs was biphasic with half-lives of 5 and 116 min. Radioactivity in liver increased rapidly, reaching a maximum of 21% of the dose within 10 min after installation and decreasing thereafter, until less than 5% of the dose was detected at 360 min. Radioactivity in intestinal contents accounted for 45% of the dose 360 min after installation. Carcass accounted for 15-30% of the dose within the time intervals investigated. Toxicokinetic parameters to describe B[a]P disposition following intratracheal administration were similar to those following intravenous injection of B[a]P. HPLC was used to identify various types of metabolites in lungs, liver, and intestinal contents at selected times after B[a]P instillation. Notably, quinones were at highest concentrations in both lung and liver 5 min after installation, accounting for 12 and 7% of organic extractable material, respectively. Covalent binding of B[a]P metabolites to DNA, RNA, and protein at 6 hrs after installation was also quantified for lung and liver. There was extensive binding of metabolites to RNA while much lesser amounts of metabolites were associated with protein and DNA in both organs. Six B[a]P:DNA adducts were detected in lung, while only three such adducts were detected in liver. ³ Biliary excretion of B[a]P was investigated in SpragueDawley rats, Gunn rats, hamsters, and guinea pigs following instillation of [³H]-B[a]P. [³H]-B[a]P was administered at concentrations ranging from 6 ng to 380 μg and biliary radioactivity was monitored for 6 hrs. In addition, tissue distribution of radioactivity was determined. Species differences in biliary excretion of B[a]P and/or metabolites were detected. Rats and guinea pigs, but not hamsters, exhibited differences in biliary excretion of low and high doses of B[a]P. Phase II metabolites of B[a]P in bile were quantified for all species. The majority of these metabolites were glucuronides and thio-ether conjugates. Enterohepatic circulation of B[a]P biliary metabolites was investigated in Sprague-Dawley rats.