Hepatic microsomal cytochrome P450 enzyme activity in relation to in vitro metabolism/inhibition of polychlorinated biphenyls and testosterone in Baltic grey seal (Halichoerus grypus)

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Abstract
Among other factors, cytochrome P450 (CYP) enzyme activity determines polychlorinated biphenyl (PCB) bioaccu-mulation, biotransformation, and toxicity in exposed species. We measured the oxidative metabolism in vitro of 12 PCB congeners, representing structural groups based on the number and position of the chlorine atoms, by the hepatic microsomes of one Baltic grey seal (Halichoerus grypus). Microsomal metabolism was observed for several PCBs with vicinal H atoms exclusively in the ortho and meta positions and without any ortho-Cl substituents (CB-15 [4,4′-Cl2] and CB-77 [3,3′,4,4′-Cl4]), vicinal meta and para-H atoms (CB-52 [2,2′,5,5′-Cl4], and −101 [2,2′,4,5,5′-Cl5]) or with both characteristics in combination with either only one ortho-Cl (CB-26 [2,3′,5-Cl3], CB-31 [2,4′,5-Cl3]) or two ortho-Cl substituents (CB-44 [2,2′,3,5′-Cl4]). To allocate PCB biotransformation to specific CYPs, the inhibitive effect of compounds with known CYP-specific inhibition properties was assessed on in vitro PCB metabolism and on regio- and stereospecific testosterone hydroxylase activities. Metabolic inhibition was considered relevant at concentrations ≤1.0 μM because these inhibitors became decreasingly selective at higher concentrations. At ortho-meta and/or meta-para vicinal hydrogens. A CYP2B form might also be involved, but this could not be proven by the results of our experiments. Defining the profiles of CYP enzymes that are responsible for PCB biotransformation is necessary to fully understand the bioaccumulation, toxicokinetics, and risk of PCB exposure in seals and other free-ranging marine mammals.