Mukhtar H, Del Tito B J, Das M, Cherniack E P, Cherniack A D, Bickers D R
Cancer Res. 1984 Oct;44(10):4233-40.
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 microM, 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.
克霉唑是一种广泛应用于皮肤科的局部应用咪唑类抗真菌剂，它被证明是苯并(a)芘（BP）表皮代谢及其微粒体酶介导的体内与新生大鼠表皮DNA以及体外与小牛胸腺DNA结合的有效抑制剂。向体外孵育系统中添加不同浓度的克霉唑，导致对照动物以及经局部应用该酶已知诱导剂预处理的动物中细胞色素P - 450依赖性微粒体芳烃羟化酶（AHH）受到剂量依赖性抑制。局部应用克霉唑对表皮AHH的抑制具有时间和剂量依赖性。克霉唑对表皮AHH的50%抑制范围为0.12至0.25微摩尔，这表明克霉唑是迄今已鉴定出的最有效的表皮AHH抑制剂之一。克霉唑在体外也被发现是环氧水解酶活性的有效抑制剂，在0.1毫摩尔时具有50%的抑制率。对大鼠表皮微粒体中BP代谢的高压液相色谱分析显示，克霉唑对代谢物形成有显著抑制作用。这在从未经处理以及经该酶诱导剂预处理的动物制备的微粒体中均有发生。此外，单次局部应用克霉唑分别导致表皮和肝脏谷胱甘肽S - 转移酶活性诱导80%和30%。将克霉唑局部应用于BALB/c小鼠皮肤显著延长了3 - 甲基胆蒽诱发皮肤肿瘤的潜伏期。这些研究表明，克霉唑是表皮BP代谢和多环芳烃（PAH）致癌物DNA结合的极其有效的抑制剂，并且是PAH解毒所需酶的增强剂。克霉唑还在体外和体内减少了BP致癌和致突变代谢物的形成，并抑制了PAH诱导的皮肤肿瘤。这些数据表明，咪唑类抗真菌剂克霉唑有望作为一种用于调节皮肤中PAH癌症风险的药物。
