Graduate Thesis Or Dissertation
 

The effects of the carcinostatic compound 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) on the hepatic microsomal enzyme systems in rats

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  • Preliminary toxicity studies of BCNU in rats revealed that significant prolongations of pentobarbital hypnosis were associated with all doses employed. Investigations were undertaken to determine the underlying mechanism responsible for this observed effect. Studies on the in vitro metabolism of pentobarbital by hepatic microsomes of BCNU-treated animals demonstrated that significant impairment of enzyme activities had occurred as early as 7 days following a single dose. The effect was dose-related, and progressed through 21 days post treatment. Kinetic changes in the microsomal enzymes were characterized by a greatly diminished maximum velocity and an unaltered Michaelis constant. Repeated administrations of phenobarbital for 5 days following a single dose of BCNU greatly increased the pentobarbital metabolizing activity given on the seventh post-BCNU day. These results suggested that the observed prolongation of pentobarbital sleeptime in rats following BCNU treatment could be largely explained by impaired metabolism of the pentobarbital in these animals. The effect of BCNU on microsomal enzyme systems was not limited to pentobarbital oxidation. Inhibition of ethylmorphine Ndemethylation, hexobarbital oxidation, aniline hydroxylation and p- nitrobenzoic acid reduction were evident at 13 days after a single dose of 30 mg/kg of BCNU. The extent of inhibition was equivalent in all systems considered. Therefore, it was apparent that BCNU affected both oxidation and reduction reactions. Moreover, metabolism of both type I and type II compounds as determined by their characteristic spectral properties upon binding to microsomes was impaired. The general depression of microsomal enzyme activities resulting from BCNU treatment could not be accounted for by deficiencies of cofactors nor actual loss of the enzymes; however, the effect was found to be closely related to significant reductions of the microsomal hemoprotein, cytochrome P-450, which is known to play an important role in the final phase of the electron transport chain. Decreases of cytochrome P-450 levels in BCNU-treated rats were again dose-related and prolonged, as observed through 21 days post treatment. Interestingly, cytochrome b₅, the second of the two hemoproteins in liver microsomes, and total microsomal protein were not significantly affected by BCNU. Parallel temporal effects on pentobarbital metabolizing activity and levels of cytochrome P-450 gave further evidence that the major effect of BCNU on the hepatic drug metabolizing systems was specifically upon cytochrome P-450. A seven-day starvation in rats resulted in severe impairment of oxidation of pentobarbital by liver microsomes. Alterations of enzyme kinetics, levels of cytochrome P-450, cytochrome b₅ and total protein were equivalent to rats at 7 days following a single dose of BCNU (30 mg/kg). Despite the fact that BCNU-treated animals exhibited tremendous decreases in food consumption and severe weight losses, the effect of BCNU on drug metabolism was independent of the nutritional status of the animals. BCNU-treated rats which were force-fed with a nutritional liquid diet were capable of maintaining their body weights at the same level. Furthermore, no significant difference was noted with respect to kinetics of pentobarbital oxidation and concentrations of cytochrome P-450 between the force-fed BCNU-treated rats and the BCNU-treated rats without the nutritional supplement. Therefore, although the same apparent effects on drug metabolizing systems were observed with either starvation or BCNU treatment, they were thought to act by different mechanisms.
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