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PubMed1982

Plasma high-density lipoproteins and hepatic microsomal enzyme induction. Relation to histological changes in the liver.

The relationship between high-density lipoproteins (HDL) in plasma and hepatic structure and microsomal function has been investigated in 54 patients undergoing diagnostic liver biopsy. Plasma HDL cholesterol and major apoproteins were correlated with hepatic histology and microsomal enzyme activity assessed directly as liver cytochrome P-450 concentration and indirectly by plasma antipyrine clearance rate. HDL cholesterol, the concentrations of apoproteins A-I and A-II, the HDL cholesterol/total cholesterol ratio and cytochrome P-450 were low in subjects with moderate or severe hepatic fatty infiltration or cirrhosis when compared with the values for subjects with a normal live. HDL cholesterol and apoprotein A-I and the HDL cholesterol/total cholesterol ratio were directly proportional to the amount of non-fatty parenchyma in the livers. Subjects with a normal liver undergoing treatment with enzyme-inducing drugs, such as phenytoin, phenobarbital and primidone, had higher HDL cholesterol, apoproteins A-I and A-II, HDL cholesterol/total cholesterol ratio, cytochrome P-450 and antipyrine clearance rate than subjects not receiving such therapy. Treatment with inducers appeared to have compensated for the effect of liver disease in lowering plasma HLD. In the entire population, and also in subjects not taking inducing drugs, when considered separately, plasma HDL cholesterol, apoproteins A-I and A-II and the HDL cholesterol/total cholesterol ratio were significantly correlated with cytochrome P-450 concentration. In subjects on enzyme inducers, HDL cholesterol and apoprotein A-I levels and the HDL cholesterol/total cholesterol ratio were proportional to the magnitude of the induction. Serum triglycerides were inversely proportional to the measures of liver microsomal enzyme activity. The lipoprotein pattern, high HDL cholesterol and apoproteins A-I and A-II, and high HDL cholesterol/total cholesterol ratio that accompany microsomal induction are characterized by a reduced risk of atherosclerotic vascular disease and a prolonged expectation of life. The plasma changes presumably reflect the effect of enzyme inducers, such as phenytoin and phenobarbital on hepatic lipids and proteins.

Adult↗
PubMed1989

Effects of enzyme induction therapy on glucose and drug metabolism in obese mice model of non-insulin dependent diabetes mellitus.

We evaluated the effects of phenobarbital, an inducer, on plasma glucose and serum immunoreactive insulin levels and on hepatic glucose and drug metabolism using an animal model of non-insulin dependent diabetes mellitus. Genetically obese (ob/ob) mice, characterized by hyperglycaemia, hyperinsulinaemia, fatty liver and obesity were selected. The impairment of diabetic state with age was associated with increased activities of NADPH producing enzymes, whereas mixed function oxidase system remained unaltered. Phenobarbital reduced serum immunoreactive insulin and plasma glucose levels and decreased gluconeogenesis. Hepatic glucose phosphorylating enzyme activity increased and glucose releasing enzyme activity decreased. The demand for NADPH in drug oxidation reactions, caused by the induction phenomenon, was reflected in the elevated activities of the NADPH producing enzymes in pentose phosphate pathway and in the activities of isocitrate dehydrogenase and malic enzyme from mitochondrial oxidation reactions. Glucose metabolism of lean littermates indicated that phenobarbital induction normalizes impaired intracellular glucose handling but leaves normal glucose metabolism unaltered. Hepatic glucose production rate was related to plasma glucose, NADPH producing enzyme activities and cytochrome P450 content in the obese and lean mice.

Animals↗
PubMed1980

Enzyme induction in a temperature-sensitive cell cycle mutant of Chinese hamster fibroblasts.

A temperature-sensitive (ts) cell cycle mutant of Chinese hamster fibroblasts with a block in G1 was investigated. Attention was on the expression of the activity of three enzymes: ornithine decarboxylase (ODC) S-adenosylmethionine decarboxylase (SAMDC), and thymidine kinase (TK). ODC and SAMDC activities are normally induced in the middle of, or late in, the G1 phase, while TK activity starts to appear at the G1/S boundary. In the ts mutant released from serum starvation at the nonpermissive temperature (40.8 degrees C), we find no effect on the expression of SAMDC activity, a significantly reduced level of ODC activity compared to the control at the permissive temperature (34 degrees C), and no induction of TK activity. Results presented here and in a previous publication (Landy-Otsuka and Scheffler, '78) suggest that the decrease in ODC activity is due to an effect of the nonpermissive temperature on a post-transcriptional step, possibly a very rapid inactivation of the enzyme. The absence of TK activity, on the other hand, appears to be due to a block in transcription at the nonpermissive temperature.

Adenosylmethionine Decarboxylase↗
PubMed2006

Atorvastatin inhibits angiotensin-converting enzyme induction in differentiating human macrophages.

Statins are effective drugs in the prevention of cardiovascular disease. Recent studies suggested that statins have additional beneficial effects on the vascular wall independent of their cholesterol-lowering effects. We investigated whether atorvastatin influences angiotensin-converting enzyme (ACE) production in differentiating human macrophages. Human peripheral blood monocytes (PBM) were isolated from fresh buffy coats. The cells were allowed to differentiate for 0-8 days in macrophage serum-free medium with 5 ng/ml granulocyte-macrophage colony-stimulating factor. Atorvastatin (0.005-0.5 microM), mevalonate (200-400 microM), geranylgeranyl pyrophosphate (1.25-2.5 microM), and/or farnesylpyrophosphate (FPP; 1.25-2.5 microM) was added on the second day of differentiation and then every other day. After incubation time, the ACE amount in intact macrophages was measured. ACE amount in PBM was low. A marked time-dependent ACE induction was noticed during differentiation of monocytes to macrophages. Atorvastatin treatment inhibited ACE induction during differentiation. In the presence of mevalonate, atorvastatin failed to downregulate ACE production. Cotreatment of the cells with atorvastatin and FPP reversed the suppressive effect of atorvastatin on ACE. In conclusion, atorvastatin inhibited ACE upregulation, normally occurring in differentiating human macrophages. This effect was mediated via the mevalonate pathway, and inhibition of FPP was probably involved. The finding that atorvastatin inhibited ACE upregulation may represent a novel pleiotropic action and an additional beneficial effect of statins in treatment of cardiovascular disease.

Adolescent↗
PubMed2004

[Estimation of level of enzyme induction of thymidine phosphorylase, dihydropyrimidine dehydrogenase, and thymidylate synthase in primary and recurrent breast cancer].

Several enzymes are closely related with the mechanism of action of fluoropyrimidine (FP). Dihydropyrimidine dehydrogenase (DPD) which catalyzes 5-fluorouracil (5-FU), thymidine phosphorylase (TP), responsible for catalyzing doxifluridine to 5-FU, and thymidylate synthase (TS) were estimated for breast cancer. TP level determined by enzyme-linked immunoabsorbant assay (ELISA), DPD level by ELISA and catalytic assay and TS level by fluorodeoxyuridine monophosphate (FdUMP) binding assay were estimated for 210 specimens from 125 consenting patients with primary or metastatic breast cancer who gave consent. TS level of T1 was higher than that of T2-4 (p < 0.05). A high positive correlation was observed between TP and DPD in the same specimen. The ratio of simultaneously resected metastasis/primary and postoperative recurrent/primary never exceeded two. Enzyme level, generally decreased with or without interventing FP therapy. Enzyme level increase was frequently observed in a series of no-drug, non-FP, and FP therapy regimens. For selection of chemotherapy or estimation of chemosensitivity, TS can be used, with either TP or DPD at first surgery, and also with intervening chemotherapy after recurrence.

Adult↗
PubMed1987

Aroclor 1254 as a 2,3,7,8-tetrachlorodibenzo-p-dioxin antagonist: effects on enzyme induction and immunotoxicity.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and Aroclor 1254 induced the cytochrome P-450 dependent monooxygenases, aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) in rat hepatoma H-4-II E cells and C57BL/6J mice. It has been proposed that both Aroclor 1254 and 2,3,7,8-TCDD induce these enzymes via a common mechanism which features initial binding to the aryl hydrocarbon (Ah) cytosolic receptor protein. The major difference between these compounds was the relative potency (i.e. 2,3,7,8-TCDD much greater than Aroclor 1254). Cotreatment of rat hepatoma H-4-II E cells or C57BL/6J mice with a dose of 2,3,7,8-TCDD which submaximally induces AHH and EROD and a dose of Aroclor 1254 which exhibited little or no induction activity resulted in significant antagonism of the induction effects of 2,3,7,8-TCDD. For example, cotreatment of C57BL/6J mice with 2,3,7,8-TCDD (15 nmol/kg) and Aroclor 1254 (25, 75 and 150 mumol/kg) resulted in up to 23% antagonism of AHH induction by 2,3,7,8-TCDD. Moreover, cotreatment with a higher dose of the 2,3,7,8-TCDD agonist (30 or 50 nmol/kg) partially reversed some of the antagonism by Aroclor 1254. In vivo antagonism was observed only at Aroclor 1254/2,3,7,8-TCDD molar ratios of 1667:1, 5000:1 and 10,000:1. Administration of 2,3,7,8-TCDD (3.72 nmol/kg) to C57BL/6J mice resulted in a 76% decrease in the splenic plaque forming cell response to sheep red blood cells. This T-cell mediated immunotoxic effect of 2,3,7,8-TCDD segregates with the Ah locus. In contrast, administration of 5, 15, 75 and 150 mumol/kg of Aroclor 1254 resulted in impairment of the immune response only at the highest dose level. However, cotreatment of mice with 2,3,7,8-TCDD (3.72 nmol/kg) and Aroclor 1254 (5, 15 or 75 mumol/kg) resulted in no significant decrease in the plaque forming cell response and complete protection from the immunotoxicity of 2,3,7,8-TCDD. Cotreatment of the mice with Aroclor 1254 (75 mumol/kg) and a higher dose of the 2,3,7,8-TCDD agonist resulted in partial reversal of the protective effects of Aroclor 1254. The in vitro and in vivo data suggest that within specific antagonist/agonist dose ratios, Aroclor 1254 can antagonize at least 2 Ah receptor-mediated effects of 2,3,7,8-TCDD, namely AHH induction and immunotoxicity.

Animals↗
PubMed1989

Occupational exposure to anaesthetics: liver injury, microsomal enzyme induction and preventive aspects.

Apart from a risk excess of liver disease among operating theatre personnel and of spontaneous abortion in women exposed during pregnancy, no definitive conclusion has been drawn as regards health impairment among anaesthesiology staff. Hepatotoxicity has been detected in experimental and epidemiological studies, suggesting a close relationship between liver disease and anaesthetics, particularly halogenated hydrocarbons (halothane and isoflurane) and nitrous oxide. The liver microsomal enzyme system has received particular attention in order to clarify the mechanism involved in anaesthetics hepatotoxicity and an increased microsomal enzyme activity has been observed in experimental conditions and in humans (both patients treated with anaesthetic mixture and anaesthesiology staff). The prevention of adverse health effect among workers of anaesthesiology staff, is based on (i) the use of less toxic anaesthetics and (ii) the control of working conditions of staff. Attention is focused on biological monitoring by means of indicators, which reflect not only the environmental pollution but can be regarded as liver response of anaesthetics exposed workers. This inductive effect is commonly considered the earliest sign caused by exposure to several chemicals and may be evaluated by means of biomarkers, among which the measure of urinary D-glucaric acid excretion is a well established non invasive tool.

Anesthetics↗
PubMed1991

Chemostat studies of microsomal enzyme induction in Saccharomyces cerevisiae.

Using cells grown in a chemostat at steady state, the levels of various components of the microsomal electron transport chain of Saccharomyces cerevisiae were examined. Cytochrome P450 haemoprotein levels measured in cells grown in medium with a dissolved oxygen concentration of 15% were induced between 10- and 20-fold over levels in cells grown in medium containing 70% dissolved oxygen concentration. An increase in the dilution rate of a culture growing in medium containing 15% dissolved oxygen resulted in an increase in the residual glucose concentration of the medium. This was paralleled by an increase in the microsomal levels of cytochrome P450. The rise could not be attributed either to increases in the concentration of ethanol in the chemostat or to an increase in the proportion of energy generated using fermentative pathways. However, this effect was not observed in cells grown in an oxygen concentration of 70%. Cytochrome b5 haemoprotein levels were also induced approximately three-fold by reducing the dissolved oxygen concentration from 70% to 15%. Changes in the medium glucose concentration from 0.03% to 1.6% (w/v) had no effect on the levels of this enzyme. Conversely, levels of cytochrome P450 NADPH reductase appeared lower in cells grown in 15% as opposed to 70% dissolved oxygen concentration. Northern slot blot analysis of total RNA extracted from chemostat-grown cells, probed with a C-14 sterol demethylase cytochrome P450 gene (cytochrome P450 LIA1), revealed a pattern of message induction which matched that of the cytochrome P450 haemoprotein, indicating that control of the levels of this enzyme was at least partially transcriptional.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Northern↗
PubMed2001

Comparisons of the effects of tamoxifen, toremifene and raloxifene on enzyme induction and gene expression in the ovariectomised rat uterus.

This study compares the actions of oestradiol, tamoxifen, toremifene and raloxifene on enzyme and gene expression in uterine tissues of ovariectomised rats over 72 h. The time-course for the induction of ornithine decarboxylase by the compounds showed a rapid biphasic response, while for creatine kinase brain type (BB) there was a continued increase over 72 h. The efficacy of induction showed that, with both markers, oestradiol gave the highest induction level, followed by tamoxifen or toremifene and then raloxifene. RT-PCR demonstrated that all compounds decreased oestrogen receptor (ER) alpha, ERbeta and ERbeta2 gene expression, 8-24 h after the first dose, suggesting that down-regulation of ER is not the primary cause of the difference in efficacy between these compounds. Using cDNA arrays, expression of 512 genes was examined in the uteri of oestradiol- or tamoxifen-treated rats. Both compounds resulted in the up-regulation of heat-shock protein 27, telomerase-associated protein 1 and secretin. However, most surprising was the marked down-regulation of Wilms' tumour and retinoblastoma genes. We speculate that this may result in a loss of regulation of the transition from the G1 to the S phase in the cell cycle and may make cells more vulnerable to the carcinogenic effects of tamoxifen in this tissue.

Animals↗
PubMed1975

Hepatic microsomal enzyme induction in rats fed varietal cauliflower leaves.

Leaves from a standard, insect-susceptible cauliflower variety and an insect-resistant strain were formulated at either 10 or 25% into semipurified diets for male and female weanling rats. After 3 weeks, relative liver weights, microsomal protein, cytochrome P-450, and activities of hepatic microsomal aminopyrine N-demethylase, aniline hydroxylase, p-nitroanisole O-demethylase, and N-methylaniline N-demethylase were determined. Growth, feed intake, and feed efficiency of male rats were not affected by the inclusion of the dried cauliflower leaf in the diet. However, female rats exhibited a depressed feed intake and increased feed efficiency with cauliflower leaf supplemental diets. Relative liver weights increased with increasing percentage of cauliflower leaves in the diet. Hepatic microsomal enzyme response to cauliflower leaf supplementation of the diet was greater in males than in females. Only aniline hydroxylase activity remained unchanged by the test diets. Male rats showed significant increases in N- and O-demethylation with both the 10 and 25% cauliflower diets, and increased values for microsomal protein and cytochrome P-450 at the 25% supplemental level. Female rats did not show significant hepatic microsomal induction from cauliflower leaf consumption at the 10% level. However, cytochrome P-450 and the metabolism of aminopyrine and p-nitroanisole were enhanced by consumption of cauliflower leaves at 25% of their diet. None of the parameters tested in this study evidenced a difference between the two cauliflower cultivars fed to either sex.

Aminopyrine N-Demethylase↗
PubMed2003

Phase 2 enzyme induction by the major metabolite of oltipraz.

Treatment for 48 h of murine Hepa 1c1c7 cells in culture with the cancer chemopreventive oltipraz (1) followed by addition of CD(3)I and immediate cell lysis yields, by LC/MS analysis, three isotopomers of the methylated pyrrolopyrazine (2), a known human metabolite of oltipraz. The major isotopomer (58%) is the one containing two CD(3)- groups attached to the pendant sulfur atoms of the pyrrolopyrazine ring, the others containing one CD(3)- and one CH(3)- group or two CH(3)- groups. It is concluded from this that the unmethylated pyrrolopyrazine (4) is the major metabolite of oltipraz. Prodrugs 5 and 6, which have been shown to rapidly generate 4 in the presence of GSH at physiological pH, induce the phase 2 enzyme NQO1 in Hepa 1c1c7 cells with potencies on par with oltipraz itself: CD(NQO1) = 14.4 +/- 1.3, 20.1 +/- 4.6, and 23.6 +/- 1.6 microM for oltipraz, 5, and 6, respectively. Pretreatment of oltipraz, 5, and 6 in cell culture media with 1 mM GSH, which is shown to immediately convert 5 and 6 to 4, followed by incubation with Hepa 1c1c7 cells shows similar potencies for oltipraz and the (decomposed) produrgs, with CD(NQO1) = 18.0 +/- 4.4 microM for 5, 17.8 +/- 0.2 microM for 6, and 13.5 +/- 1.4 microM for oltipraz. Treatment with compound 6 of murine hepatoma cells containing a luciferase gene under the control of the antioxidant response element (ARE) from the mouse heme oxygenase (ho-1) gene elicits induction of luciferase activity, CD = 35.8 +/- 2.8 microM, somewhat greater than the potency than oltipraz itself. Western blots of nuclear proteins isolated from Hepa 1c1c7 cells and probed with anti-Nrf2 indicate that as compared to vehicle DMSO, compound 6 stimulates nuclear translocation of Nrf2 from the cytosol. From this study, it is concluded that the major metabolite of the cancer chemopreventive oltipraz is a phase 2 enzyme inducer of comparable potency that activates the ARE and initiates nuclear translocation of transcription factor Nrf 2.

Animals↗
PubMed1998

Drug-metabolizing enzyme induction by 2,2'-dipyridyl, 1,7-phenanthroline, 7,8-benzoquinoline and oltipraz in mouse.

1. Changes in the major hepatic drug-metabolizing enzymes by compounds identified as atypical inducers (multienzyme response but devoid of cytochrome P450-inducing ability) in rat were investigated in mouse. Animals were treated with 1,7-phenanthroline, 2,2'-dipyridyl, 7,8-benzoquinoline and oltipraz at 75 and 150 mg/kg daily for 3 days. 2. UDP-glucuronosyltransferase (UGT) activities showed only limited changes, UGT activity towards 4-nitrophenol and 1-naphthol was induced by the 75 mg/kg dose of 2,2'-dipyridyl and UGT activity towards morphine was induced by 150 mg/kg doses of 7,8-benzoquinoline and oltipraz. UGT activity towards oestrone was not induced by any treatment regimen and showed a decrease following treatment with the lower dose of 7,8-benzoquinoline. 3. In contrast with the limited effect on UGT activities, glutathione S-transferase and NAD(P)H:quinone oxidoreductase activities were significantly elevated by most compounds. Glutathione S-transferase activity was significantly elevated by the 150 mg/kg dose of 1,7-phenanthroline (73%), 2,2'-dipyridyl (52%) and oltipraz (75%), and also the lower dose of 1,7-phenanthroline (47%). NAD(P)H:quinone oxidoreductase activity was significantly elevated by the higher dose of all N-heterocycles (155-323%) as well as the lower dose of 1,7-phenanthroline (180%). 4. In contrast with the effect previously seen in rat, 7,8-benzoquinoline significantly elevated mouse cytochrome P450 concentration but not 7-ethoxyresorufin O-dealkylase activity. As in rat, no N-heterocycle-containing compound significantly elevated pentoxyresorufin O-dealkylase activity. 5. Overall, mouse show a more limited response in the range of drug-metabolizing enzymes induced by N-heterocycles compared with rat, but as in rat, cytochrome P450 was largely unaffected.

2,2'-Dipyridyl↗
PubMed1978

[Estradiol reception and enzyme induction in mouse mammary gland neoplasms].

Under study was the dependence of mammary gland tumors growth on ovarian hormones level in C3H and DD mice. Tumors arising spontaneously were transplanted to 30--40 mice of the same strain, and tumors of the first passage were studied. The experiments were undertaken on ovariectomized and hormone-treated animals; the latter were given estradiol-benzoate and progesterone injections weekly during a month in the dosage of 5 mcg and 400 mcg per animal, respectively. Out of 6 tumors in C3H mice no one responded to ovariectomy or hormone administration by changes in the growth rate. Of 25 tumors in DD mice the transplants of one were found to respond to the ovarian hormones administration by a substantial increase of the growth rate. Only in these tumors a high level of estradiol receptors was noted. It was established that these tumors responded to the estradiol treatment by induction of the hexokinase and glucose-6-phosphatedehydrogenase activities. It is supposed that the changes in the enzymes activity under estradiol treatment in mammary gland tumors are indicative of their hormone-dependence.

Animals↗
PubMed1967

Enzyme induction in green monkey kidney cultures infected with simian adenovirus.

Thymidine kinase was induced after infection of an established strain of green monkey kidney cells (CV-1) with simian adenovirus SV15. Increased levels of thymidine kinase were first observed 8 to 10 hr postinoculation (PI), and the levels increased four- to eightfold by 16 to 24 hr PI. A transient increase (1.5- to 3-fold) of deoxyribonucleic acid (DNA) polymerase activity was also observed about 18 hr PI, but the level of deoxycytidylic deaminase was not enhanced. The inductions of thymidine kinase and DNA polymerase were not obtained when protein synthesis was inhibited with 10(-5) M cycloheximide. However, the enzyme increases did take place when infected cultures were treated with 1-beta-D-arabinofuranosylcytosine (ara-C), an inhibitor of DNA synthesis and SV15 replication. The incorporation of tritium-labeled thymidine (H(3)-dT) into DNA was also stimulated 8 to 24 hr after infection with SV15.

Adenoviridae↗
PubMed2000

Accumulation pattern and biotransformation enzyme induction in rainbow trout embryos exposed to sublethal aqueous concentrations of 3,3',4,4'-tetrachlorobiphenyl.

Accumulation pattern of 3,3',4,4'-tetrachlorobiphenyl (PCB 77) and the exposure time needed to activate the monooxygenase (EROD) and conjugation (GST) enzyme systems of fish at the advanced embryonic stage were studied. Eyed stage embryos of rainbow trout (Oncorhynchus mykiss) were exposed to sublethal doses (0, 1, 10, and 100 micrograms/l) of PCB 77. Results indicated direct accumulation of the chemical into the eggs, but the exposure time was not long enough for PCB 77 to reach constant steady state. However, at the two lowest test concentrations (1 microgram/l and 10 micrograms/l) a temporary plateau at chemical accumulation was reached at the third exposure day (185 and 1221 ng PCB/g egg w.w). At the highest concentration (100 micrograms/l) the decrease in the accumulation rate was already evident after the first day (2182 ng PCB/g egg w.w). The chemical uptake increased again at day 7 in all the exposure groups. That event could have been caused by the increased metabolic rate of the embryos in preparation for the upcoming hatching event. The microsomal CYP1A monooxygenase system (EROD) was shown to be a sensitive indicator of embryonic exposure, being induced at the low (1 microgram/l, 182 ng/g egg) PCB concentration and after a short (3 day) exposure time. The conjugation enzyme system (GST) was shown to be functioning already at the advanced embryonic stage, although no response to the studied chemical stress was detected.

Animals↗