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Clotrimazole, an Inhibitor of Epidermal Benzo(a)pyrene Metabolism and DNA Binding and Carcinogenicity of the Hydrocarbon¹

Department of Dermatology, Case Western Reserve University [H. M., B. J. D., M. D., E. P. C., A. D. C., D. R. B.], and the Veterans Administration Medical Center [H. M., B. J. D., M. D., E. P. C., A. D. C., D. R. B.], Cleveland, Ohio 44106

Clotrimazole, a topically applied imidazole antifungal agent widely used in dermatological practice, was shown to be a potent inhibitor of the epidermal metabolism of benzo(a)pyrene (BP) and its microsomal enzyme-mediated binding both to neonatal rat epidermal DNA in vivo and to calf thymus DNA in vitro. Varying concentrations of clotrimazole added to in vitro incubation systems resulted in a dose-dependent inhibition of cytochrome P-450-dependent microsomal aryl hydrocarbon hydroxylase (AHH) in control animals as well as in animals pretreated with topical application of known inducers of the enzyme. Inhibition of epidermal AHH by topically applied clotrimazole was time and dose dependent. The 50% inhibition of clotrimazole for epidermal AHH ranged from 0.12 to 0.25 µM, which suggests that clotrimazole is among the most potent inhibitors of epidermal AHH yet identified. Clotrimazole was also found to be a potent inhibitor of epoxide hydrolase activity in vitro with a 50% inhibition at 0.1 mM. High-pressure liquid chromatographic analysis of the metabolism of BP in rat epidermal microsomes revealed substantial inhibition of metabolite formation by clotrimazole. This occurred in microsomes prepared from untreated as well as animals pretreated with inducers of the enzyme. Furthermore, a single topical application of clotrimazole resulted in 80 and 30% induction of epidermal and hepatic glutathione S-transferase activity, respectively. Topical application of clotrimazole to the skin of BALB/c mice substantially increased the latent period for the development of skin tumors by 3-methylcholanthrene.

These studies indicate that clotrimazole is an extremely potent inhibitor of epidermal BP metabolism and of the DNA-binding of polycyclic aromatic hydrocarbon (PAH) carcinogens, and is an enhancer of enzymes necessary for detoxification of the PAH. Clotrimazole also reduces the formation of carcinogenic and mutagenic metabolites of BP in vitro and in vivo and inhibits induction of skin tumors by the PAH. These data indicate that the imidazole antifungal clotrimazole offers promise as an agent useful for the modulation of PAH cancer risk in the skin.

¹ Supported in part by NIH Grant ES-1900 and research funds from the Veterans Administration.

² To whom requests for reprints should be addressed, at Veterans Administration Medical Center, 10701 East Boulevard, Cleveland, OH 44106.

Received 12/ 7/83. Accepted 6/28/84.