Effect of dietary level of sulfur-containing amino acids on liver drug-metabolizing enzymes, serum cholesterol and urinary ascorbic acid in rats fed PCB.
(41/55)
Effects of dietary level of sulfur-containing amino acids (S-AA) on liver drug-metabolizing enzymes, serum cholesterol and ascorbic acid metabolism in growing rats fed diets containing 300 ppm of polychlorinated biphenyls (PCB) were investigated. Maximum gain in body weight was observed with 0.5% S-AA diets with or without PCB addition. Metabolic parameters increased by PCB were liver weight, activities of hepatic aminopyrine N-demethylase and aniline hydroxylase, serum total cholesterol, serum high density lipoprotein cholesterol, serum corticosterone and urinary metabolites of the glucuronic acid pathway including ascorbic acid, glucuronic acid and glucaric acid. In the PCB-treated animals, maximum values of liver weight, aminopyrine demethylase activity, serum cholesterol, serum corticosterone, urinary ascorbic acid and glucaric acid were obtained with about 0.8% S-AA. For the maximum induction of these metabolic responses, 0.5% S-AA was not enough. Urinary glucuronic acid and the ratio of lower density lipoprotein cholesterol versus high density lipoprotein cholesterol were decreased with a supplement of S-AA to PCB-containing diets. (+info)
Protective role of thiols in cyclophosphamide-induced urotoxicity and depression of hepatic drug metabolism.
(42/55)
One of the serious toxicities of cyclophosphamide chemotherapy is urotoxicity. In addition to causing leukopenia, high-dose cyclophosphamide caused both depression of hepatic microsomal enzyme activities and extensive urinary bladder damage, suggesting that a common biochemical mechanism may be responsible for both of these effects. Administration of 180 or 200 mg cyclophosphamide per kg to Wistar rats caused 41 to 67% decrease in aryl hydrocarbon hydroxylase activity, a 21 to 54% decrease in aminopyrine demethylase activity, and a 34 to 40% decrease in cytochrome P-450 content. This dose of cyclophosphamide also caused hematuria as well as necrosis and edema in the urinary bladder. Administration of N-acetylcysteine or sodium-2-mercaptoethane sulfonate (mesnum) with cyclophosphamide, while not protecting against leukopenia, protected against the enzymatic inactivation and urotoxicity. The biochemical basis of these observations is discussed. The results suggest that a common metabolite of cyclophosphamide, most probably acrolein, is responsible for both of these undesirable effects of cyclophosphamide therapy. Use of combinations including cyclophosphamide and an appropriate thiol may increase the therapeutic index of this drug. (+info)
Effect of phenobarbital on toxicity of pyrrolizidine (Senecio) alkaloids in sheep.
(43/55)
The effect of prolonged phenobarbital (PB) administration on the toxicity of Senecio jacobaea (SJ) was studied in sheep. Hepatic microsomal mixed function oxidase (MFO) activity was monitored. Pentobarbital sleeping times were decreased after 17 d of treatment, indicating initial induction of MFO. At 105 d of treatment, hepatic microsomal aminopyrine N-demethylase activity and cytochrome P-450 levels were increased (P less than .05) as a result of PB administration. No differences (P greater than .05) were observed in activity of microsomal epoxide hydrolase, glutathione S-transferase or liver glutathione as a result of SJ and (or) PB. Epoxide hydrolase activity in control sheep was about fivefold higher than values previously reported for rats. Liver Cu concentration was increased (P less than .05) in sheep receiving PB and SJ when compared with controls, but no differences (P greater than .05) were observed in the hepatic intracellular distribution of Cu as a result of PB and(or) SJ. Histopathological examination of liver revealed greater incidence and severity of lesions in animals receiving SJ, but PB did not appear to potentiate SJ intoxication. The results suggest that MFO induction by PB does not increase the susceptibility of sheep to SJ intoxication. Sheep possess a high activity of hepatic microsomal epoxide hydrolase which could account for their resistance to SJ intoxication. (+info)
Haem and drug-metabolizing enzymes in regenerating rat liver.
(44/55)
Various parameters of haem and drug metabolism were measured during the course of liver regeneration after two-thirds hepatectomy. Partial hepatectomy produced a significant depression in delta-ALA synthetase and delta-ALA dehydratase, and induction in haem oxygenase at an early stage of regeneration. The values returned to normal within 7-14 days. These changes were also accompanied by a marked decline in benzo(a)pyrene hydroxylase and aminopyrene demethylase. The level of glutathione and the activity of glutathione reductase also increased during the early stage of proliferation. The increased level of glutathione with concomitant decrease in drug-metabolizing enzymes and induction in haem oxygenase could be considered as a protective mechanism for the detoxication process, although a contribution from other biotransforming mechanisms cannot be excluded. (+info)
Kinetic evidence for heterogeneous responsiveness of mixed function oxidase isozymes to inhibition and induction by allylisopropylacetamide in chick embryo liver.
(45/55)
Changes in hepatic mixed function oxidase kinetics after administration of allylisopropylacetamide (AIA) to chick embryos indicate that the activities of different cytochrome P-450 isozymes, including those participating in the metabolism of the same substrates, can be simultaneously increased and inhibited by a single xenobiotic. Up to 4 h after administration in ovo, or in vitro, AIA exclusively inhibited mixed function oxidases. At 24 h after administration in ovo, AIA simultaneously decreased the Vmax of the isozymes active in 7-ethoxycoumarin deethylation and in biphenyl and antipyrine hydroxylations in control liver and caused new isozymes with higher Km and Vmax values to appear. At the same time, AIA increased the Vmax values for isozymes active in aminopyrine demethylation and decreased the Vmax for benzo(a)pyrene hydroxylation (EC 1.14.14.1). As an inhibitor, AIA did not exhibit substrate selectivity but tended to inhibit isozymes with higher substrate affinity noncompetitively and lower affinity isozymes competitively. Competitive mechanisms and generalized P-450 breakdown could only partially account for the inhibition of mixed function oxidases by AIA. The inhibition at low doses of AIA (0.1 to 0.3 mg/egg) occurred without any decrease in P-450 and at higher doses it exceeded and was more persistent than the decrease in P-450. The data indicate that in addition to the known mechanisms for mixed function oxidase inhibition by AIA there is another noncompetitive mechanism independent of P-450 breakdown. As an inducer, AIA, like phenobarbital rather than beta-naphthoflavone increased the metabolism of aminopyrine and the concentration of Mr = 50,000 and 51,000 proteins preferentially. However, unlike either, AIA selectively induced new high Km and Vmax isozymes active toward 7-ethoxycoumarin, biphenyl, and antipyrine and increased the concentration of a Mr = 53,000 protein. These actions distinguish AIA from either the phenobarbital or polycyclic hydrocarbon class of inducers. The simultaneous inhibition by AIA of higher affinity isozymes with selective induction of low affinity isozymes produced a "crossover effect" in which after AIA administration the rates of 7-ethoxycoumarin deethylase and biphenyl and antipyrine hydroxylases were decreased at low and increased at high substrate concentrations. The findings demonstrate the complexity and selectivity of AIA's actions as a mixed function oxidase inhibitor and inducer and illustrate the potential heterogeneity of responses that can occur in the mixed function oxidase system after exposure of an organism to a xenobiotic. (+info)
Effects of dietary and in vitro 2(3)-t-butyl-4-hydroxy-anisole and other phenols on hepatic enzyme activities in mice.
(46/55)
Six phenols [2(3)-t-butyl-4-hydroxyanisole (BHA), 2-t-butylphenol, 4-methoxyphenol, 4-methylmercaptophenol, t-butylhydroquinone and 2,6-di-t-butylphenol] previously shown to be inhibitors of benzo(a)pyrene-induced neoplasia, were examined for their ability to induce in vivo changes in hepatic mono-oxygenase and detoxication enzyme activities, and to act as mono-oxygenase inhibitors when added in vitro. (1) Generally it was found that cytochrome P450 levels were depressed, only 2,6-di-t-butylphenol caused a 2-fold induction (2) Mono-oxygenase activities were significantly altered; BHA and 2,6-di-t-butylphenol caused microsomes to show substantial increases in aniline hydroxylase and peroxidase activities. These microsomes, along with 4-methoxyphenol microsomes, also showed a substantial reduction in DNA binding of benzo(a)pyrene (BaP) metabolites relative to metabolism. (3) Detoxication enzymes glutathione S-transferases and epoxide hydratase were readily induced, the order of effectiveness being: BHA approximately 2,6-di-t-butylphenol greater than 4-methoxyphenol greater than 2-t-butylphenol approximately t-butylhydroquinone (4-methylmercaptophenol failed to induce). (4) In vitro ability to inhibit BaP metabolism and DNA-binding ability was: 2,6-di-t-butylphenol greater than or equal to BHA approximately 2-t-butylphenol greater than t-butylhydroquinone greater than 4-methylmercaptophenol greater than 4-methoxyphenol. (5) Ability in vitro to discharge the activated oxygen complex of cytochrome P450 was: 2,6-di-t-butylphenol approximately 2-t-butylphenol greater than BHA greater t-butylhydroquinone greater than 4-methylmercaptophenol greater than 4-methoxyphenol. The results are consistent with the theory that inhibition of neoplasia is related to inducibility of detoxication enzymes, though alterations in cytochrome P450 could play a significant role in some cases. (+info)
Species and strain differences in the butylated hydroxytoluene (BHT)-producing induction of hepatic drug oxidation enzymes.
(47/55)
Five week-old, Wistar-JCL male and female rats and C57BL/6N male mice give a 0.5% butylated hydroxytoluene (BHT)-containing diet for 6 days produced a marked increase in hepatic weight and microsomal protein content. However, the augmentations of cytochrome P-450 content and drug oxidation activities were much more significant, i.e. 2.5-fold and more than three-fold increases were observed on a body weight basis, respectively. BHT-induced cytochrome P-450 cannot be distinguished from phenobarbital (PB)-induced cytochrome in many respects we have examined: i.e. 1) a broad substrate specificity; 2) absence of the blue shift in the CO-binding difference spectrum; 3) no rise in the peak height ratio of ethylisocyanide difference spectrum; 4) absence of alpha-naphthoflavone inhibition of p-nitroanisole demethylase activity; 5) marked increases of 50,000 and 54,000 molecular weight polypeptides in SDS-polyacrylamide gel electrophoresis. However, the induction of 46,000 molecular weight polypeptide by BHT in rats was more conspicuous than that by PB, and this induction was not observed in mice. In contrast to this marked induction, the administration of BHT to MC nonresponsive DBA/2N mice produced neither heptic enlargement nor induction of cytochromes, but did not produce an extremely high mortality. (+info)
Hepatic aminopyrine N-demethylase system: interaction of aminopyrine with microsomal cytochrome P-450.
(48/55)
Interaction of aminopyrine with microsomal membrane-bound cytochrome P-450 was studied spectrophotometrically at various pH. Aminopyrine-induced type I spectral change in untreated rat microsomes was observed in neutral and alkaline media, and the absorption magnitude between peak and trough in the spectra increased markedly by increasing pH. On the other hand, an anomalous spectral change (lambda max, 425 nm; lambda min, 410 nm) was obtained in acid medium, and the absorption magnitude of the anomalous spectral change was enhanced by decreasing pH. The spectral dissociation constant for the anomalous aminopyrine-binding reaction at pH 6.32 was about one order of magnitude greater than that for the type I binding reaction at pH 8.22. The type of aminopyrine-induced spectral change differed depending upon the age and pretreatment of animals. Neonatal microsomes elicited only the anomalous spectral change in all pH media. Liver microsomes from 3-methylcholanthrene-pretreated rats showed a reverse type I spectral change. Antipyrine produced only a reverse type I spectral change in all microsomes tested, and the absorption magnitude was enhanced by decreasing the pH. In the presence of a saturated concentration of a reverse type I compound, i.e., ethanol or antipyrine, aminopyrine induced the type I spectral change, even in acid medium. The binding mechanism of cytochrome P-450 with aminopyrine is discussed on the basis of these results. (+info)