SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
Tyrosine alpha ketoglutarate transaminase, which is rapidly induced by various agents, shows circadian rhythmicity in the intact rat. This rhythmicity is only slightly altered after adrenalectomy, indicating that adrenal hormones do not play a major role in the metabolic control of the activity of tyrosine alpha ketoglutarate transaminase. On the other hand, phenylalaninepyruvate transaminase, which is not inducible over the same time period, does not show circadian variation. The results suggest that the sensitivity of an enzyme's regulating system to inducing agents may be related to the inherent circadian rhythm of the enzyme.
After cultivation of Streptomyces hydrogenans in the presence of different steroids the activity of both 3 alpha, 20 beta-hydroxysteroid dehydrogenase and 3 beta, 17 beta-hydroxysteroid dehydrogenase was determined in the cell homogenate of the microorganism. By comparing the efficacy of the steroids to increase enzyme activities, steroids could be divided into 3 groups: a) steroids which stimulated preferentially the activity of 3 alpha, 20 beta-hydroxysteroid dehydrogenase (e. g., corticosterone), b) steroids which stimulated preferentially 3 beta, 17 beta-hydroxysteroid dehydrogenase (estradiol-17 beta), and c) those behaving intermediately (e. g., progesterone, 5 alpha -dihydrotestosterone). Highest 3 beta, 17 beta-hydroxysteroid dehydrogenase activity could be measured 2 h after addition of 5 alpha-dihydrotestosterone to the culture medium. The activity of 3 alpha, 20 beta-hydroxysteroid dehydrogenase, however, increased continuously up to 4 h. 3 alpha, 20 beta-hydroxysteroid dehydrogenase and 3 beta, 17 beta-hydroxysteroid dehydrogenase syntheses seemed to be controlled by steroids in a non-coordinate manner.
The enzyme activity of the rat hindgut microflora maintained in an anaerobic two-stage continuous culture was compared with that of rat cecal contents. A qualitative comparison (API ZYM) showed a high degree of similarity between the two populations. Quantitative determinations showed that azoreductase, beta-glucosidase, nitrate reductase, and nitroreductase activities were comparable, and that beta-glucuronidase activity was very low in the culture. beta-Glucuronidase, beta-glucosidase, and nitrate reductase activities were induced within the culture by their respective substrates. Bile acids influenced microbial activity in vitro, with cholic acid inducing beta-glucosidase, azoreductase, and beta-glucuronidase activities and decreasing nitrate reductase activity. Chenodeoxycholic acid increased beta-glucosidase and beta-glucuronidase activities and decreased azoreductase, nitrate reductase, and nitroreductase activities in vitro. These studies demonstrate that the rat hindgut microflora may be successfully cultured in vitro and suggest control mechanisms that regulate the metabolic activity of these organisms in vivo.
Rats were exposed for four weeks either to air or to vapours of chloroform, carbon tetrachloride or 1,1-dichloroethylene given either as a constant concentration (continuous profile) or as repeated exposures for 6 hr per day, 5 days per week (fluctuating profile). Vapour concentrations were used such that the total exposure (concentration x time) was the same for the two profiles. Within each group, some animals received the enzyme-inducing agents, phenobarbitone or 1,3-butanediol, in their drinking water. Separate experiments were conducted to determine the influence of enzyme inducers and vapour concentration on chlorocarbon uptake and metabolism. In the case of chloroform, hepatic injury was more severe in animals exposed to constant vapour concentration, while dichloroethylene was more toxic when given as a fluctuating profile, especially in butanediol-treated rats. Carbon tetrachloride hepatotoxicity was similar in the two exposure profiles but was exacerbated by butanediol treatment. Butanediol-treated animals in the fluctuating profile group showed evidence of developing cirrhosis. These results could not be fully explained on the basis of the effect of enzyme inducers and exposure profile on amount of agent metabolized. Both the amount of toxic metabolites and the temporal pattern of their formation appear to be important determinants of liver injury.
Explore the source record for details and available documents.
The synthesis of Cu,Zn SOD by rat lung increases spontaneously in the fetus in late gestation and during exposure of neonatal and adult rats to greater than 95% O2. To explore the regulation of these increases, we measured rat lung Cu,Zn SOD synthesis and activity. We also cloned and sequenced a rat lung Cu,Zn SOD cDNA that was used to measure Cu,Zn SOD mRNA concentration. We found that (a) under normal gestational and postgestational conditions the synthesis of this enzyme was regulated pretranslationally; (b) the increased synthesis that occurs under hyperoxia (greater than 95% O2), was pretranslationally mediated in otherwise unmanipulated neonatal rats but translationally controlled in hyperoxic adult rats; and (c) in lungs of rats made tolerant to greater than 95% O2 by allowing 24 h rest in air after an initial 48 h in greater than 95% O2, the increased Cu,Zn SOD synthesis that occurred during the second period of hyperoxia was regulated pretranslationally. We conclude Cu,Zn SOD gene expression in the lung is developmentally regulated under normal conditions and in response to an oxidant challenge. Tolerance, whether endogenous or induced, appears to require the accumulation of increased amounts of Cu,Zn SOD mRNA.
Chronic exposure to high doses of phenobarbital (PB) causes hepatocellular adenomas in both mice and rats and hepatocellular carcinomas in some strains of mice. Long-term PB therapy has not been found to cause human tumors. PB is not DNA reactive, and most genotoxicity tests have yielded negative results. PB has been extensively studied as an epigenetic, rodent liver tumor promoter. At exposures causing rodent liver tumors, PB has measurable effects on hepatocytes: PB inhibits cell-to-cell communication; PB induces enzymes, including P450 cytochromes; PB stimulates proliferation and inhibits apoptosis of hepatocytes in neoplastic foci. Threshold exposures for some of these endpoints coincide with the threshold exposure for tumorigenesis.
Explore the source record for details and available documents.
Male F344/NCr rats, 6 wk old, were fed 500 ppm of phenobarbital (PB) or equimolar doses of either 5-ethyl-5-phenylhydantoin (EPH) or 5,5-diethylhydantoin (EEH) in diet for 2 wk and hepatic cytochrome P-450-mediated alkoxyresorufin O-dealkylase and aminopyrine N-demethylase activities were determined. Both PB and EPH greatly increased P-450-mediated enzyme activities in rat liver while EEH was ineffective. To evaluate the hydantoins as tumor promoters, 5-wk-old male F344 rats were given a single i.p. injection of 75 mg N-nitrosodiethylamine/kg body weight. Beginning 2 wk later, they were placed either on normal diet or diet containing 500 ppm of PB or equimolar doses of EPH or EEH for the remaining experimental period. Control groups received an i.p. injection of saline followed by each of the test diets. Animals were sacrificed at either 52 or 78 wk. PB and EPH significantly enhanced the development of hepatocellular foci and hepatocellular adenomas at 52 wk and hepatocellular carcinomas at 78 wk in N-nitrosodiethylamine-initiated rats. Neither the incidence of hepatocellular neoplasms nor the number and size of hepatocellular foci was significantly increased by EEH. At 78 wk, both PB and EPH enhanced the development of thyroid follicular cell neoplasms in N-nitrosodiethylamine-initiated rats while no such enhancement was observed with EEH. Thus, EPH, a long-acting sedative/anticonvulsant, like the structurally similar PB, promoted hepatocellular and thyroid follicular cell carcinogenesis and induced the PB-inducible form(s) of cytochrome P-450 (P-450b) in rats. In contrast, EEH unlike barbital failed to promote hepatocellular and thyroid follicular cell carcinogenesis and also failed to induce PB-inducible form(s) of cytochrome P-450 in rats.
Nifedipine (NF), sparteine (SP), mephenytoin (MP) and antipyrine (AP) were administered simultaneously ("cocktail" design) to 15 healthy subjects, including 4 poor metabolizers (PM) of SP and 4 PMs of MP, on three different occasions: without pretreatment, after pentobarbital (PB) pretreatment and together with cimetidine (cim). Concentrations of AP, NF, its pyridine metabolite 2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate-methylester (M-O), SP, dehydrosparteine (DHS) were determined in plasma; 2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate-monomethyle ster (which is ester hydrolyzed M-O), SP, DHS, 4-hydroxymephenytoin, AP and metabolites 3-hydroxymethylantipyrine, norantipyrine and 4-hydroxyantipyrine were measured in urine. Clearance of NF had increased 270% after PB and decreased 32% with cim. Area under the plasma-concentration time curve of M-O and urinary excretion of 2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate-monoethyles ter had also decreased after PB. Neither extensive metabolizers nor PMs of SP and MP were sensitive to PB treatment, but sparteine clearance was reduced 55% by cim in extensive metabolizers and 59% in PMs. Ratio SP/DHS in urine was hardly influenced by cim. AP oxidation was significantly induced and inhibited by PB and cim, respectively. The cocktail study design seems to be suitable to assess induction and inhibition of the metabolism of the applied model substrates, which are metabolized by at least partly independent isozymes of the cytochrome P-450 system, simultaneously.
Male and female CD rats were administered one of two dose levels of clofibrate, gemfibrozil, or bezafibrate daily by oral gavage for a period of 14 days in order to establish an empirical data base using the Charles River CD rat with a single class of drugs against which the potency of novel proprietary compounds could be compared. Subsequent gross examination of the liver indicated significant and dose-related increases in relative and absolute liver weights in males following clofibrate and gemfibrozil. In females, absolute and relative liver weights were significantly elevated to a similar degree with either dose of gemfibrozil, and absolute liver weights were higher in clofibrate-dosed animals. Bezafibrate had no effect on female liver weights. Clofibrate and gemfibrozil increased hepatic palmitoyl CoA beta-oxidation in both sexes; however, clofibrate had the greater effect in males and gemfibrozil had the least effect in females. Bezafibrate treatment resulted in a very pronounced elevation of palmitoyl CoA beta-oxidation in the males but had no similar effect in the females. Concurrent ELISA analysis for cytochrome CYP4A revealed very good correspondence between beta-oxidation and cytochrome induction for each of the three compounds in males, but other cytochromes were not greatly affected, except CYP1A1 which was elevated in bezafibrate-dosed females. For males, further analysis for markers of cellular proliferation, namely cyclin-dependent kinases (CDK) and proliferating cell nuclear antigen (PCNA), indicated dose-related increases for both with clofibrate, increases at the high dose for gemfibrozil, and, for PCNA, a dose-related increase for bezafibrate. In females, both markers for cell proliferation showed either slight or no increases following any of the three drug treatments. These results demonstrate clear sex-dependent differences in terms of relative potency in the hepatic response of the Sprague-Dawley-derived rat to these peroxisome proliferators. Bezafibrate is most potent and gemfibrozil is least potent in stimulating peroxisome-associated beta-oxidation and cytochrome P450 4A induction in the males. Even though gemfibrozil significantly increased liver weights, beta-oxidation and cytochrome P450 4A in the females increased only after clofibrate treatment, although to a lesser degree than in the males administered the same dose. Similar sex-related differences were observed for cell proliferation. In conclusion, sex-related differences were noted in the potency to stimulate acyl Co-A oxidation, its association with hepatomegaly, and the stimulation of cell proliferation, but CYP4A induction always accompanied any substantial drug-dependent increases in beta-oxidation.
Troglitazone (TGZ), a 2,4-thiazolidinedione antidiabetic, causes hepatotoxicity in 1.9% of patients. TGZ is an inducer of, and substrate for, hepatic P450 3A. Microsomal metabolism yields a benzoquinone (TGZQ) and reactive intermediates. Kassahun et al. [Kassahun et al. (2001) Chem. Res. Toxicol. 14, 62-70] have trapped the intermediates as thioester, thioether, and disulfide conjugates of glutathione and found five conjugates in rat bile. The thioether was substituted in the chromane moiety. We have investigated the effect of the P450 3A inducer, dexamethasone (DEX), on metabolism of TGZ and TGZQ in rats and assessed the compounds' cytotoxicity. TGZ-glucuronide and sulfonate were confirmed as principal biliary metabolites of TGZ (50 mg/kg, iv). Bile from noninduced animals also contained a TGZ-glutathione thioether adduct (ML3) but it was substituted in the thiazolidinedione moiety. Pretreatment with DEX (50 mg/kg/day for 3 days) resulted in a 2-5-fold increase in the biliary concentration of ML3 and a 2-fold increase in the concentration of TGZQ, which was commensurate with the induction of hepatic P450 3A. Three of the known glutathione-conjugated metabolites were also found. TGZQ (50 mg/kg, iv) was metabolized to an analogue of one of the TGZ-glutathione thioesters and a glutathione adduct of TGZQ hydroquinone after DEX pretreatment. TGZ quinol glucuronide was a biliary metabolite of TGZ and TGZQ. Its formation would represent deactivation of TGZQ. TGZ was toxic to rat hepatocytes and Hep-G2 cells at concentrations exceeding 50 and 25 microM, respectively, after 24 h. In contrast, TGZQ was nontoxic to rat hepatocytes and toxic to Hep G2 cells only at concentrations exceeding 100 microM. Our results show that TGZQ as well as TGZ yields reactive metabolites in vivo, and that bioactivation is enhanced by induction of P450 3A. However, hepatotoxicity is unlikely to be due to either TGZQ or its metabolites.
Glutamine synthetase in the developing retina of the chick embryo can be induced to increase by certain corticosteroids. The inductive effectiveness of various natural corticosteroids has been examined in organ cultures of embryonic retina and correlated with specific groupings on the steroid molecules.
Six normal male volunteers ingested a dose of 400 mg free testosterone daily as tablets over 21 days. By the end of treatment intravenous antipyrine half-life had decreased significantly from 8.0 +/- 2.7 to 5.7 +/- 2.6 hr. The subjects eliminated testosterone from serum more rapidly on the twenty-first day of testosterone ingestion than on the first day. Serum albumin, bilirubin, prothrombin, alanine-amino-transferase, and alkaline phosphatases were unchanged during the experiment. It is concluded that oral testosterone treatment induces the hepatic drug-metabolizing system including that of testosterone.
Intravenous injections to rabbits of perfluorocarbon emulsion containing perfluorodecaline (10 ml/kg, equivalent to 1.3 g of perfluorodecaline per 1 kg of body weight) produced a 2-4-fold increase of cytochrome P-450 content in the liver microsomes within 3-4 weeks. Cytochrome P-450 induction was followed by activation of the liver monoxygenase system evaluated by the rate of antipyrine excretion from the blood. On the 1st day after administration perfluorodecaline caused an insignificant (14%) inhibition of the monoxygenase system.
Psoralens, tricyclic furocoumarins with potent photosensitizing properties in the skin, are now widely used in the treatment of several dermatologic diseases. In this study, the metabolism of 4,5',8-trimethylpsoralen (TMP) and 8-methoxypsoralen (8-MOP) was studied in mouse liver. Orally administered TMP is transformed into several metabolites, the major one of which is 4,8-dimethyl-5'-carboxypsoralen (DMCP) in both humans and mice. Orally administered 8-MOP is metabolized into at least 5 fluorescent moieties, including 8-hydroxypsoralen, the 4'5'-dihydro-diol of 8-MOP, and furocoumaric acid. The effects of 3 psoralens, 8-MOP, TMP, and isopsoralen (angelicin) on hepatic microsomal drug-metabolizing enzymes and cytochrome P-450 were assessed in mice and rats. Administered orally to CD-1 mice daily for 6 days, 8-MOP caused twofold to threefold increases in hepatic aryl hydrocarbon hydroxylase (AHH), ethylmorphine N-demethylase, and cytochrome P-450. The absorbance maximum of the induced cytochrome was at 450 nm. Aniline hydroxylase activity was unchanged. Chronic administration of 8-MOP to Skh:hairless-1 mice caused significant enhancement of hepatic ethylmorphine N-demethylase and cytochrome P-450 but had no effect on AHH, whereas chronically administered TMP had no significant effect on any of these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
Aryl hydrocarbon hydroxylase (AHH) and dimethylnitrosamine demethylase (DMND) activities in pulmonary and hepatic tissues of male Sprague-Dawley rats were assayed following pretreatment with known inducers (benzo[a]pyrene, 3-methylcholanthrene, Aroclor 1254, phenobarbital) and with main-stream (MS) and side-stream (SS) cigarette smoke condensates and their related fractions. Biochemical assays by spectrophotofluorimetry (AHH activity) and spectrophotometry (DMND activity) and by a biological assay (Ames test) were performed to detect AHH and DMND induction. Ames test proved to be much less sensitive than the spectrophotofluorimetric analysis for AHH determination. Both main-stream and side-stream cigarette smoke condensates and some fractions, containing water-soluble bases, water-insoluble bases, and polycyclic aromatic hydrocarbons, were found to induce AHH activity in lung and liver, the lung being induced to the greatest extent. The highest levels of AHH inducibility were found for the SS-smoke condensate and related fractions. In particular, the insoluble bases fractions gave the highest induction. On the contrary, pulmonary DMND activity was not affected by pretreatment with the same materials, while hepatic DMND response was only minimally induced by Aroclor and phenobarbital treatment.