Polyamines and drug oxidations.
The addition of spermine or of spermidine to rat liver assay systems produced marked changes in a number of microsomal drug oxidations. The hydroxylation of aniline and the N-demethylation of ethylmorphine were both enhanced with concentrations of 1-10 mM spermine or of spermidine. The results with putrescine on ethylmorphine metabolism were less dramatic, and no effect could be observed with putrescine in studies with other drug substrates. In contrast to the enhancing effects, inhibition was observed when spermine or spermidine was added to p-nitroanisole O-demethylation assay mixtures, and no effect was observed in assays for acetanilide hydroxylation. The inhibiting and enhancing effects of the polyamines can be observed in assays containing liver preparations from both male and female rats, and those from rats pretreated with phenobarbital or 3-methylcholanthrene. In all studies, the alterations were kinetically noncompetitive. The effects were shown to be independent of the NADPH-generating system and the cation requirements, and were not mediated through an interaction with NADPH-cytochrome c reductase. The possibility is considered that the enhancing and inhibiting effects may be related to the ability of these polycations to bind to microsomal membranes and cause alterations at different sites of substrate interaction.
D000083:Acetanilides / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D000840:Anisoles / Q000378:metabolism; D005260:Female; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006900:Hydroxylation; D066298:In Vitro Techniques; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009022:Morphine Derivatives / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011073:Polyamines / Q000494:pharmacology*; D051381:Rats
D000083:Acetanilides; D000814:Aniline Compounds; D000840:Anisoles; D009022:Morphine Derivatives; D004364:Pharmaceutical Preparations; D011073:Polyamines; D008748:Methylcholanthrene; D005954:Glucosephosphate Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase; C005306:4-nitroanisole; D010634:Phenobarbital