Dependence of hydrogen peroxide formation in rat liver microsomes on the molecular structure of cytochrome P-450 substrates: a study with barbiturates and beta-adrenoceptor antagonists.
In the present study, the molecular structure of xenobiotics has been successfully linked to their effect on the oxidase activity of cytochrome P-450, determined as microsomal hydrogen peroxide formation. A homologous series of 5-alkyl-5-ethyl barbiturates and a heterologous series of beta-adrenoceptor antagonists was used. The logarithm of the rate of microsomal hydrogen peroxide formation could be correlated with the logarithm of the apparent partition (n-octanol/buffer) coefficient for the barbiturate derivatives according to a parabolic function. The statistics of the correlation improved considerably by applying a bilinear model in order to fit the data. This probably indicates that both transport of the substrate to cytochrome P-450 and interaction with hydrophobic substrate binding sites of cytochrome P-450 are involved in the modulating effect of substrates on the oxidase function of cytochrome P-450. With the series of beta-adrenoceptor antagonists no clear-cut structure activity relationship with regard to the oxidase activity was apparent at first sight. However, when the inhibitory effect of the beta-antagonists on the 'cytochrome P-450 metabolic intermediate (MI) complex' formation that occurs during the microsomal biotransformation of 33 microM tofenacine was studied a relationship with the lipophilicity could be demonstrated. It is known that MI complex formation occurs with specific subforms of cytochrome P-450. By using this inhibitory activity of the beta-adrenoceptor antagonists, the interaction of the compounds becomes restricted to these specific subforms of cytochrome P-450. In both the oxidase activity as well as the MI complex formation phenobarbital induced cytochrome P-450 is involved.(ABSTRACT TRUNCATED AT 250 WORDS)
Bast
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Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Goossens
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PA
Savenije-Chapel
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EM
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001463:Barbiturates / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D013056:Spectrophotometry, Ultraviolet
D000319:Adrenergic beta-Antagonists; D001463:Barbiturates; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D006861:Hydrogen Peroxide; D010634:Phenobarbital