Clotrimazole, an inhibitor of epidermal benzo(a)pyrene metabolism and DNA binding and carcinogenicity of the hydrocarbon

H. Mukhtar, B. J. Del Tito, M. Das, Evan Paul Cherniack, A. D. Cherniack, D. R. Bickers

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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 cyctochrome 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 modification of PAH cancer risk in the skin.

Original languageEnglish
Pages (from-to)4233-4240
Number of pages8
JournalCancer Research
Volume44
Issue number10
StatePublished - Dec 6 1984
Externally publishedYes

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Clotrimazole
Benzo(a)pyrene
Hydrocarbons
DNA
Aryl Hydrocarbon Hydroxylases
Polycyclic Aromatic Hydrocarbons
Skin
Enzymes
Microsomes
Epoxide Hydrolases
Neoplasms
Methylcholanthrene
Antifungal Agents
Glutathione Transferase
Carcinogens

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mukhtar, H., Del Tito, B. J., Das, M., Cherniack, E. P., Cherniack, A. D., & Bickers, D. R. (1984). Clotrimazole, an inhibitor of epidermal benzo(a)pyrene metabolism and DNA binding and carcinogenicity of the hydrocarbon. Cancer Research, 44(10), 4233-4240.

Clotrimazole, an inhibitor of epidermal benzo(a)pyrene metabolism and DNA binding and carcinogenicity of the hydrocarbon. / Mukhtar, H.; Del Tito, B. J.; Das, M.; Cherniack, Evan Paul; Cherniack, A. D.; Bickers, D. R.

In: Cancer Research, Vol. 44, No. 10, 06.12.1984, p. 4233-4240.

Research output: Contribution to journalArticle

Mukhtar, H, Del Tito, BJ, Das, M, Cherniack, EP, Cherniack, AD & Bickers, DR 1984, 'Clotrimazole, an inhibitor of epidermal benzo(a)pyrene metabolism and DNA binding and carcinogenicity of the hydrocarbon', Cancer Research, vol. 44, no. 10, pp. 4233-4240.
Mukhtar, H. ; Del Tito, B. J. ; Das, M. ; Cherniack, Evan Paul ; Cherniack, A. D. ; Bickers, D. R. / Clotrimazole, an inhibitor of epidermal benzo(a)pyrene metabolism and DNA binding and carcinogenicity of the hydrocarbon. In: Cancer Research. 1984 ; Vol. 44, No. 10. pp. 4233-4240.
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abstract = "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 cyctochrome 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 modification of PAH cancer risk in the skin.",
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