Measurement and Modulation of Cytochrome-P450-Dependent Enzyme Activity in Cultured Human Keratinocytes

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Abstract
The metabolism of xenobiotics by the epidermis can be studied in vitro by using keratinocyte cultures. We present a simple and rapid method for determining the activity of cytochrome P450-dependent enzymes (ethoxycoumarin-O-de-ethylase, ECOD, and ethoxyresorufm-O-deethylase, EROD) in intact cultured human keratinocytes. Using this method, we studied the effect of a well-known cytochrome P450 inhibitor (proadifen) and of two inducers (phenobarbital and 3-methyl-cholanthrene). As reported in vivo some imidazole compounds (miconazole and econazole) induce ECOD activity at low concentrations and inhibit it at high concentrations. In contrast, two other imidazoles (clotrimazole and sulconazole) only had an inducing effect on ECOD activity. Imidazole itself had no apparent effect on ECOD activity. In conclusion, this model appears to be useful for studying the biotransforming activity of human skin. It allows a rapid evaluation of the inducing/inhibitory effects of xenobiotics.

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