Relative contribution of various forms of cytochrome P450 to the metabolism of benzo[a]pyrene by human liver microsomes

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Abstract
A variety of cytochromes P450 have been implicated in the hepatic metabolism of benzo[a]pyrene (BP), including forms that are constitutively expressed and those that are highly inducible. In the present study the metabolism of BP to organic solvent-soluble derivatives by eight forms of cytochrome P450 isolated from rat liver and by a series of 11 human liver microsomal samples was investigated. The relative contribution of specific P450 forms to the human hepatic metabolism was evaluated. A 4-fold variation in formation of total organic solvent-soluble BP metabolites was observed, as well as differences in the regio- and stereo-selectivity of this metabolism between the three individuals studied. The levels of expression of cytochromes P450 from five gene sub-families, as determined by Western blot analysis, did not show any correlation with the rate of BP metabolism to organic solvent-soluble derivatives in these livers. No reduction in metabolism was observed in three livers in which either the debrisoqulne P450 (P450IID1) was not expressed or bufuralol 1-hydroxylase activity was low. Of six different antibodies to forms of rat liver P450 tested, only those to P450s MCla (P450IA2), MClb (P450IA1) and UT (P450IIA1) consistently inhibited BP metabolism. This inhibition was generally limited and rarely exceeded 30%. An antibody to cytochrome P450 PB (P450 did, however, inhibit the formation of metabolites at the 4,5- and 9,10-positions of BP by microsomal fractions of livers from one individual who had been receiving the drug phenytoin. These data indicate that several forms of P450 in human liver are involved in the metabolism of BP and that both constitutively expressed as well as inducible forms are important in its disposition in man.

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