Hepatic mixed function oxygenase activity in rats during cholestasis following 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) treatment Public Deposited

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  • Rats were given single i.p. injections of BCNU to investigate changes in hepatic cytochrome P-450 content and specific activity in male rats. Microsomal P-450 levels were unchanged from 6 hours to 7 days after BCNU treatment but by day 21 they had decreased 45%. Ethylmorphine N-demethylase activity (nm product x nm P-450⁻¹ x minute⁻¹) was only 67% of controls 14 days after BCNU treatment while ethylmorphine 0-deethylase activity only fell 12%. Metabolism of benzo(a)pyrene and 7-ethoxycoumarin was not decreased to the extent of ethylmorphine N-demethylation. β-naphthoflavone increased 7-ethoxycoumarin metabolism more in BCNU pretreated rats than in controls. Microsomal heme oxygenase activity was slightly elevated in BCNU treated rats 14 days after dosing. Delta-aminolevulinic acid synthetase activity was only 60% of controls in the liver homogenates of BCNU treated rats. No difference in microsomal total heme was detected. Partial purification of P-450 from control and BCNU treated rat hepatic microsomes was achieved. Reduced, CO exposed preparations from treated rats had a bathochromic shift of 1.3 nm as compared to controls. Reconstituted systems with P-450 from controls had approximately 3 times higher ethylmorphine N-demethylase activity than similar systems using P-450 from BCNU treated rats. Differences between electrophoresis banding patterns were also observed. These results support the hypothesis that different P-450 isozymes exist in the treated animals. Many of the changes seen in drug metabolism and hepatic heme metabolism after BCNU treatment mimic those reported from other laboratories in rats with cholestasis. BCNU produces cholestasis in rats and this may explain how the drug causes prolonged differences in P-450 content and specific activity.
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