Paradoxical effects of cobaltous chloride treatment on 2-methylnaphthalene disposition and hepatic cytochrome P-450 content in carp.

Abstract

Effects of cobaltous chloride (CoCl2) treatment on the disposition of 2-methylnaphthalene (2-MeNap)-derived radioactivity was studied in adult carp. The fish were treated with CoCl2 (60 mg/kg, ip) or an equivalent volume of saline (control) 36 and 12 hr before 2-MeNap administration (5 mg/kg, ip). Carp were killed 12, 24, 48 and 72 hr later. CoCl2-treated carp had less 2-MeNap-derived radioactivity in gallbladder bile and a greater amount in the liver at all of these times. Solvent extraction of bile revealed that virtually all of the radioactivity was due to polar 2-MeNap metabolites in both groups. Solvent extraction of liver showed that the greater total amount of 2-MeNap-derived radioactivity in the CoCl2 treatment group was due to a greater amount of parent compound being present; amount of polar 2-MeNap metabolites in the liver of CoCl2-treated carp and control carp was similar. Inasmuch as 2-MeNap metabolism in carp is thought to involve monooxygenation in the liver, our results suggest that the altered hepatobiliary disposition of 2-MeNap in CoCl2-treated carp may be due to depressed 2-MeNap metabolism by liver microsomal enzymes. However, total hepatic cytochrome P-450 content and activity of an associated monooxygenase enzyme (7-ethoxycoumarin-O-deethylase) were similar in CoCl2-treated and control carp throughout the study. To resolve this paradox (apparent depression of hepatic 2-MeNap metabolism by CoCl2 but lack of effect on hepatic cytochrome P-450 content and 7-ethoxycoumarin-O-deethylase activity), it is suggested that a minor form of cytochrome P-450 may be responsible for hepatic 2-MeNap metabolism in carp and be selectively inhibited or degraded by CoCl2. Inherent in this postulate is the assumption that this minor form of cytochrome P-450 does not contribute significantly to total cytochrome P-450 content of carp liver or 7-ethoxycoumarin-O-deethylase activity.