In vitro and in vivo inhibition of pulmonary cytochrome P450 activities by piperine, a major ingredient of piper species.

ABSTRACT

In vitro and in vivo modulation of drug metabolizing enzymes by piperine was investigated in microsomes of rats and guinea pigs. In vitro piperine caused concentration related inhibition (50% at 100 microM) of arylhydrocarbon hydroxylase (AHH) and 7-ethoxycourmarin deethylase (7ECDE) activities, which were comparable in control and 3-methylcholanthrene (3MC) treated rats. In guinea pig microsomes however, piperine caused strong inhibition at lower concentrations (35% at 10 microM) and relatively much lesser inhibition with further increase in piperine concentrations. A Dixon plot of the kinetic data of both AHH and 7ECDE indicated noncompetitive inhibition with a Ki of approx. 100 microM. In vivo, piperine given at a dose of 25 mg/kg body wt to rats caused a maximal inhibition at 1 hr of both the enzymes, while only AHH returned to normal value within 4 hr. Similarly, upon daily treatment of piperine (15 mg/kg body wt) to rats for 7 days, 7ECDE was consistently inhibited, while AHH showed faster recovery. Piperine thus appeared to cause differential inhibition of two forms of cytochrome P450 and thus would accordingly affect the steady-state level of those drugs metabolized by these pulmonary forms of cytochromes P450.