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Biomedical subjects

S Orrenius

Publications and source records attributed to S Orrenius.

At least 289 records · Page 16Linked to original sources
PubMed1980

The influence of inducers on drug-metabolizing enzyme activity and on formation of reactive drug metabolites in the liver.

A variety of environmental agents can affect the rate of drug biotransformation in the liver by induction of drug-metabolizing enzymes. Both phase I and phase II reactions (the first and second stages of drug metabolism) may be influenced, and epoxide hydrolase, glucuronosyl transferases and glutathione-S-transferases are examples of enzymes which, in addition to the cytochrome P-450-linked monooxygenase system, are readily inducible by environmental agents. Phenobarbitone and 3-methylcholanthrene are the most widely studied representatives of two major classes of inducers. Induction of hepatic drug-metabolizing enzymes is often associated with enhanced detoxification of drugs and other foreign chemicals that are metabolized by these enzymes. However, during recent years, the effect of induction on many compounds has been found to be the opposite, i.e. toxicity is increased. This is true for most hepatotoxic drugs and major groups of chemical carcinogens; experiments with carbon tetrachloride, bromobenzene and benzo[alpha]pyrene serve to illustrate this point in the present paper. It is concluded that the toxicological significance of induction of drug-metabolising enzymes may differ from one substrate to another, and that general conclusions about the beneficial or harmful effects of induction should not be drawn.

Animals↗
PubMed1980

On the effect of cellular nucleophiles on the binding of metabolites of 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene and 9-hydroxybenzo(a)pyrene to nuclear DNA.

The binding to DNA of products resulting from the further activation of trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene and 9-hydroxybenzo(a)pyrene was studied in several incubation systems. In a system containing purified DNA and rat liver microsomes, products of 9-hydroxybenzo(a)pyrene were the predominant binding species. In a system containing isolated rat hepatocytes, the total binding was much lower, and products of trans-7,8-dihydroxy-7, 8-dihydrobenzo(a)pyrene predominated. Both the total amounts and the ratios of the bound species were altered by the addition of various soluble nucleophiles to the incubation system. The binding of 9-hydroxybenzo(a)pyrene to both nuclear and purified DNA was decreased in the presence of "non-specific" protein in the incubate. A decrease in the binding of trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene to either purified or nuclear DNA was seen after the addition of active cytosol, but not with protein alone. Either denaturation of the cytosol, or depletion of glutathione by diethylmaleate treatment, partially negated this effect. We conclude that the binding of benzo(a)pyrene metabolites to DNA in the cell is decreased by soluble nucleophiles, and that this trapping of metabolites is selective. 9-Hydroxybenzo(a)pyrene metabolites are removed by non-specific protein binding, whereas removal of trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene metabolites requires higher affinity binding or enzymatic conjugation.

Animals↗
PubMed1980

Metabolism of extracellular glutathione in rat small-intestinal mucosa.

Metabolism of exogenous glutathione was investigated in suspensions of freshly isolated rat small-intestinal mucosal cells. The cells catalyzed the oxidation of reduced glutathione (GSH) to glutathione disulfide (GSSG). Neither serine . borate nor methionine significantly influenced this reaction. Formed GSSG was further metabolized as indicated by its disappearance from the medium. Degradation of GSSG was stimulated by methionine and inhibited by serine . borate. Separation and identification of GSSG metabolites were achieved by high performance liquid chromatography. The results indicate that the preferred route for GSSG metabolism to the constituent amino acids in small intestine, is by hydrolytic removal of the two gamma-glutamyl groups of GSSG to yield cystinyl-bisglycine which is subsequently hydrolyzed to cystine. gamma-Glutamyltransferase activity was compared in isolated intestinal, kidney and liver cells using gamma-glutamyl-p-nitrocarboxyanilide as substrate. Kidney cells were approximately 5-fold and 150-fold more active than intestinal and liver cells, respectively. Serine . borate markedly inhibited, and glycyl-glycine stimulated, hydrolysis of gamma-glutamyl-p-nitrocarboxyanilide in all cell types confirming the involvement of gamma-glutamyltransferase in the reaction. The hydrolysis of gamma-glutamyl-p-nitrocarboxyanilide was inhibited to approximately the same extent by either GSH or GSSG suggesting that both compounds interact at the donor site of gamma-glutamyltransferase. Comparison of the rates of glutathione metabolism by isolated intestinal and kidney cells suggests that the intestinal contribution to the degradation of extracellular glutathione may be physiologically more important than has previously been assumed.

Animals↗