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At least 667 records · Page 37Linked to original sources
PubMed1994

Specific binding of dehydroepiandrosterone sulfate to rat liver cytosol: a possible association with peroxisomal enzyme induction.

Incubation of [3H]dehydroepiandrosterone sulfate (DHEAS) with rat liver cytosol demonstrated its specific binding with a dissociation constant of 72 +/- 14 nM and a maximal binding capacity of 312 +/- 105 fmol/mg cytosol protein. The binding correlated with the amount of cytosol protein, and depended on time, temperature and pH, with equilibrium being reached after 6 h at 0 degrees C and pH 7.5. Boiling or treatment of the cytosol with proteases or sulfhydryl-blocking reagents affected the binding. The apparent molecular mass of the binding entity was estimated to be 160-230 kDa by HPLC gel filtration. In competitive binding studies, free steroids, including dehydroepiandrosterone (DHEA), sulfatase substrates and ligands of organic anion binders such as ligandin and fatty acid binding protein, had no effect on the [3H]DHEAS binding. Peroxisome proliferators also had no effect, except Wy-14,643. Competition with various steroids related to DHEAS revealed strict structural requirements for DHEAS binding, in which epiandrosterone sulfate was almost as effective as unlabeled DHEAS in inhibiting [3H]DHEAS binding. These findings indicated the presence of a binding protein highly specific to DHEAS in rat liver cytosol. The DHEAS binding in liver cytosol was 2-fold higher in male than in female rats. The cytosolic DHEAS binding was highest in the liver, followed by the kidney and heart. The possibility of association between the DHEAS binding and DHEA induction of peroxisomal beta-oxidation is discussed.

Animals↗
PubMed1988

DNA alkylation by 1,2-dimethylhydrazine in the rat large intestine and liver: influence of diet and enzyme induction.

Male Wistar rats were fed a semi-purified diet (MID - minimal inducing diet) with or without addition of 50 ppm of beta-naphthoflavone (BNF) for 1 week. After 1 week the rats were dosed with 20 mg/kg of 1,2-dimethylhydrazine (DMH) subcutaneously and killed at various time intervals from the injection. Enzyme levels were determined in microsomal and cytosolic fractions prepared from the liver and the intestinal mucosa. Feeding of BNF for 1 week caused a 6.5-fold increase of 7-ethoxyresorufin (7-ERR) deethylase in the colon as compared to the controls, but did not alter glutathione (GSH) content nor glutathione-S-transferase (GSHST) activity. Hepatic cytochrome P-450 and 7-ERR deethylation were not significantly altered by feeding of BNF at this concentration, whereas GSH and GSHST were increased by a factor of 1.6 and 2, respectively. In the DMH-dosed rats, O6-methylguanine was formed to a greater extent in the BNF-treated colon than in the controls at 1, 12 and 24 h, whilst N7-methylguanine levels were essentially the same in the induced and uninduced rats. No significant difference was found in the degree of hepatic DNA alkylation at any time points. As shown by our results, the nature of the diet would appear to be able to modulate the rate of metabolic activation of DMH and its binding to DNA in the target organ.

1,2-Dimethylhydrazine↗
PubMed1972

Folate deficiency after anticonvulsant drugs: an effect of hepatic enzyme induction?

Serum and red cell folate levels were reduced in 59% and 58% respectively of 75 children with epilepsy attending a residential school. The degree of folate deficiency was significantly related to increased hepatic microsomal enzyme activity, assessed from increased urinary excretion of D-glucaric acid and also correlated with the daily dose of anticonvulsant taken. Anticonvulsant drugs are known to have inducing properties, and since folate is required as a cofactor in drug hydroxylations it is suggested that folate depletion results from increased demand for the cofactor after induction of drug-metabolizing enzymes. As folate deficiency may ultimately limit drug metabolism this hypothesis would explain why blood phenytoin levels decrease and fit control may worsen after correction of folate deficiency in epileptic patients.

Adipates↗
PubMed1986

Paracetamol toxicity: is enzyme induction important?

A female patient receiving carbamazepine developed severe liver damage after an overdose of paracetamol. Antidotal therapy was not administered because her plasma paracetamol concentration was below that normally indicating the need for such therapy. Subsequently, carbamazepine was readministered and resulted in marked induction of the metabolism of a single dose of paracetamol. Antidotal therapy may be indicated if the plasma paracetamol concentrations are 70% or more of those shown in the conventional treatment line, if the patients are also receiving enzyme-inducing drugs.

Acetaminophen↗
PubMed1993

Peroxisomal enzyme induction uncoupled from enhanced DNA synthesis in putative preneoplastic liver foci of rats treated with a single dose of the peroxisome proliferator nafenopin.

Putative preneoplastic foci of spontaneous origin could be detected in the livers of 2 year old, untreated male Wistar rats. The unaltered and preneoplastic hepatocytes showed an identical expression of the peroxisomal marker enzyme acyl-CoA oxidase, as determined by immunohistochemical staining. A single dose of the peroxisome proliferator (PP) nafenopin (NAF) induced the enzyme predominantly in hepatocytes around the central venules and cell replication mainly in the periportal areas. However, upon one NAF application almost all of the preneoplastic foci showed a considerably weaker immunoreaction for peroxisomal acyl-CoA oxidase than the surrounding tissue. Concomitantly NAF elevated replicative DNA synthesis index in foci up to approximately 40%, while replication of hepatocytes in the unaltered portion of the livers increased only slightly to moderately. In conclusion, NAF-induced peroxisomal acyl-CoA oxidase and replicative DNA synthesis seem not to be necessarily coupled within the same liver cell. Furthermore, preneoplastic foci responded rather to the cell replicative than to the peroxisomal effects of NAF, suggesting that the PP-induced growth stimulus is of particular significance for the carcinogenic action of this class of compounds.

Acyl-CoA Oxidase↗
PubMed1988

Microsomal enzyme induction, lipoproteins and atherosclerosis.

The liver is the principal site for the synthesis and elimination of lipoproteins circulating in plasma, and alterations in hepatic function influence plasma lipoprotein levels. High HDL-C/T-C and apo A-I/apo B ratios, which are characteristic of a low coronary risk, have been typical of healthy subjects with high microsomal enzyme activity in the liver. Microsomal enzyme inducing drugs such as phenytoin, phenobarbital and carbamazepine, and also alcohol, influence serum lipid and apoprotein concentrations. The inducers increase the concentrations of hepatic microsomal enzyme and apo A-I mRNA, and also proteins and phospholipids. They similarly increase serum HDL-C and apo A-I levels and the HDL-C/LDL-C ratio, powerful protective factors against coronary heart disease. These parameters parallel hepatic protein and phospholipid concentrations, and microsomal enzyme activity as assessed by liver cytochrome P-450 or antipyrine kinetics. Serum LDL-C levels are inversely proportional to hepatic cytochrome P-450 concentrations. Experimental studies indicate that phenobarbital retards cholesterol accumulation in the arterial wall and the formation of atherosclerotic plaque. A decreased mortality rate from coronary heart disease has been reported for subjects who take enzyme inducers, drugs or alcohol, whereas impairment of hepatic microsomal function may promote atherogenesis. In addition to drugs non-pharmacological factors such as dietary constituents and physical exercise may influence hepatic microsomal function and hence improve the serum lipoprotein profile. These observations, which connect microsomal inducers, liver lipids and proteins, serum lipids and apoproteins characteristic of a low risk of atherosclerotic disease and low incidence of coronary deaths, lead to the conclusion that the activation of liver microsomal function can prevent atherogenesis in man.

Arteriosclerosis↗