Effect of protein deficiency on the inducibility of the hepatic microsomal drug-metabolizing enzyme system. I. Effect on substrate interaction with cytochrome P-450.

TitleEffect of protein deficiency on the inducibility of the hepatic microsomal drug-metabolizing enzyme system. I. Effect on substrate interaction with cytochrome P-450.
Publication TypeJournal Article
Year of Publication1973
AuthorsHayes JR, Mgbodile MU, Campbell TC
JournalBiochemical pharmacology
Date Published1973 May 1
KeywordsAppetite, Body Weight, Cytochrome P-450 Enzyme System, Dietary Proteins, Enzyme Induction, Kinetics, Liver, Microsomes, Liver, Organ Size, Phenobarbital, Phosphatidylcholines, Protein Binding, Protein Deficiency, Proteins

Male, weanling rats divided into three groups were maintained for 15 days on a semipurified diet containing either 5% casein fed ad lib. (group 1), 20% casein pair-fed to group 1 (group 2), or 20% casein fed ad lib. (group 3). After each group was further subdivided, animals were injected i.p. on days 11, 12, 13 and 14 with either 0.9% saline or phenobarbital (80 mg/kg) in 0.9% saline. Twenty-four hr after the last injection, animals were decapitated and liver microsomes were prepared. Contents of microsomal protein, phosphatidylcholine and cytochrome P-450 were measured and used as bases of expression for spectral dissociation constants (Ks) and maximal spectral changes (ΔAmax) associated with the binding of ethylmorphine and aniline to the cytochrome P-450 hemoprotein of microsomes. Phenobarbital administration increased microsomal protein, cytochrome P-450, and phosphatidylcholine in all three dietary groups; however, in all groups, the increase in P-450 was relatively greater than that for phosphatidylcholine. Protein deficiency (group 1 vs 2) decreased P-450 and microsomal protein, but had no effect on phosphatidylcholine contents. The effect of total food restriction (group 2 vs 3) on each of these parameters was not significant. These data suggest that a portion of the induced cytochrome P-450 binding sites may be dependent on an association with phosphatidylcholine. The fraction of such phosphatidylcholine-associated sites relative to the total sites was greater during protein deficiency and was in agreement with a greater ΔAmax per nanomole P-450 for ethylmorphine. Phenobarbital induction decreases the proposed fraction of phosphatidylcholine-associated P-450 sites relative to the total P-450 sites and results in a decrease in the ΔAmax per nanomole P-450 for ethylmorphine. Phenobarbital increased the ΔAmax per milligram of microsomal protein for aniline, which paralleled the increase in total P-450, thus indicating that the type II site may be independent of any association of cytochrome P-450 with phosphatidylcholine. These results indicate that phosphatidylcholine may play an important role in distinguishing the effects of dietary deficiency on type I substrate binding and the corresponding capacity for induction of the rat liver microsomal enzyme system.

star, openSupported in part by Public Health Service Research Grant No. 1 RO1 ES00336 from the National Institute of Health, Division of Environmental Health Sciences. Presented in part at the American Institute of Nutrition Meetings, Federation of American Societies for Experimental Biology, Atlantic City, New Jersey, April, 1972; Fedn Proc.31, 734, 1972. Portions of these data were submitted by J. R. Hayes and M. U. K. Mgbodile in partial fulfillment of requirements for the Ph.D. degree.

Alternate JournalBiochem. Pharmacol.
PubMed ID4695663
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