Hepatotoxicity and pulmonary toxicity of pennyroyal oil and its constituent terpenes in the mouse

Pennyroyal oil, an aromatic mint-like oil used as a flavoring and fragrance agent and as a herbal medicine, caused acute hepatic and lung damage at doses of 400 mg/kg, ip, and higher in male Swiss-Webster mice. Cellular necrosis was localized to the centrilobular regions of the liver and bronchiolar epithelial cells of the lung. Capillary gas chromatographic analysis of samples of pennyroyal oil that were obtained from health food stores showed the presence of several monoterpene constituents. R-(+)-Pulegone was the major terpene and constituted greater than 80% of the constituent terpenes in the oils that were examined. Pulegone and two other constituent terpenes, isopulegone and menthofuran, were found to be both hepatotoxic and lung toxic. Based on results of histologic scoring of necrosis, plasma GPT elevations, and hepatic glutathione depletion, R-(+)-pulegone is the terpene primarily responsible for the tissue necrosis. Furthermore, results of toxicity tests with several congeners of R-(+)-pulegone, including the enantiomeric S-(?)-pulegone, strongly implicated the α-isopropylidene ketone group as the structural unit required for eliciting hepatotoxicity, although the configurational orientation of the methyl group can modulate the hepatotoxic response.