Xenobiotic Metabolism

Environmental Health Sciences

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Abstract

Pulegone is a monoterpene found in the essential oil of several mints, including Pennyroyal. These mints are used in flavoring food and beverages. Pennyroyal and Pennyroyal oil have also been used as an abortifacient. The use of Pennyroyal oil, which contains about 85% pulegone, as an abortifacient has resulted in serious toxicity and death. Pulegone has been nominated to the NTP for toxicity and carcinogenicity studies. As part of those studies disposition studies in rats and mice are being conducted which have determined that pulegone is rapidly absorbed and excreted. At doses from 0.8 to 80 mg/kg, mice excrete about 80% of the dose in urine and 20% in feces in 24 hr. Rats eliminate about 50% in urine and 20% in feces in 24 hr. Tissue concentrations are thus lower in mice than rats. Male rats tend to have higher tissue concentrations, especially in kidney, than female rats but this sex difference is not seen in mice. The higher tissue concentrations in male rats are probably due to binding to alpha2u globulin. Chronic exposure to chemicals which bind to this protein often lead to kidney tumors in the male rat. Metabolism of pulegone in mice differs from rats in that several mercapturic acid and aromatic metabolites identified in rat urine are not present in mouse urine. This difference in metabolic profile could be due to the much more rapid biotransformation in mice leading to hydroxylation and conjugation of pulegone. This is a detoxification process. Mercapturic acids arise from reaction of GSH with alkylating agents. Formation of alkylating agents often correlates with toxicity. Thus, pulegone may be expected to be less toxic to mice than rats. Lidocaine and prilocaine are local anesthetics approved for use in humans. Lidocaine can be metabolized to 2,6-xylidine. Prilocaine can be metabolized to o-toluidine. Both 2,6-xylidine and o-toluidine have been shown to be rodent carcinogens; however the carcinogenic potential of the parent compounds have not been adequately investigated. Further, investigations into the genotoxicity of either lidocaine, prilocaine, 2,6-xylidine, or o-toluidine have been inconclusive in Samonella assays. The present work is an effort to better characterize the mutagenic potential of this class of anesthetics. Work in progress involves using the Ames mutagenicity test to detect possible compound-derived mutagenic metabolites excreted in urine. To date, male rats have been dosed by gavage with either lidocaine, prilocaine, 2,6-xylidine, and o-toluidine (all doses at 100 mg/kg, n=4 rats/treatment group). Urine from one animal from each group has been fractionated on HPLC for analysis in the Ames test. If mutagenicity is detected in any fraction, mutagenic metabolites will be isolated and characterized using LC/MS. Methods development with the Ames test is currently underway.