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PubMed1989

Enzyme induction by eating charcoal-grilled steak with no effect on blood lipids.

1. There has been interest in the suggestion that enzyme-inducing drugs, such as anticonvulsants, may produce beneficial changes in lipoprotein levels, in particular a rise in the ratio of high density lipoprotein cholesterol to total cholesterol. 2. This controlled study observed the effects of diets of charcoal or oven-cooked beef on antipyrine clearance (a commonly used measure of drug metabolizing capacity), the apparent oral clearance of phenacetin (a measure of cytochrome P448-dependent enzyme activity) and blood lipids in 18 healthy volunteers. 3. Charcoal-cooked beef increased antipyrine clearance by an average of 20% (P less than 0.059) and increased the apparent oral clearance of phenacetin fivefold (P less than 0.01). In contrast, oven-cooked beef did not significantly alter either measure of microsomal function. Neither diet had any effects on blood lipids. 4. We conclude that the type and degree of enzyme induction achieved by this type of dietary manipulation does not produce beneficial changes in lipoprotein profiles. A previously noted rise in high density lipoprotein cholesterol levels in volunteers fed charcoal-cooked beef may have been due to the effects of charcoal formed by charring of the beef during cooking.

Antipyrine↗
PubMed1984

Selectivity of mixed-function oxygenase enzyme induction in flounder (Pseudopleuronectes americanus) collected at the site of the Baie Verte, Newfoundland oil spill.

A marked level of mixed-function oxygenase (MFO) enzyme induction was observed in kidney but not in liver tissues of winter flounder collected at the site of a spill of No. 2 fuel oil in Newfoundland. A number of MFO-linked, electron transport components including cytochrome P450, cytochrome P450 reductase and cytochrome b5 reductase were also slightly elevated in kidney tissues of fish at the oiled site. The results obtained in this particular field trial demonstrate that reliance on the measurement of liver MFO parameters alone could lead to false negatives in biological monitoring programs. The study also indicates that the exclusive use of liver tissues to investigate the induction potential of various chemicals should be avoided.

Animals↗
PubMed1985

Guinea-pig model of halothane-associated hepatotoxicity in the absence of enzyme induction and hypoxia.

Halothane anesthesia (1%) administered in 21% oxygen for 4 hr to an outbred strain of guinea pig in the absence of enzyme induction resulted in liver damage in 40 of the 65 animals studied. Necrosis was either confluent around the central veins or in scattered foci throughout the lobules. Damage was present on the second and third days after anesthesia. By day 7 the livers had recovered, evidenced by lack of histological changes and normal serum alanine aminotransferase activity. Administration of halothane in 14 or 80% inspired oxygen did not alter the extent or incidence of liver damage. Major end-metabolites of halothane biotransformation (2-chloro-1,1-difluoroethylene, 2-chloro-1,1,1-trifluoroethane, inorganic fluoride and trifluoroacetic acid) were identified at each oxygen concentration. The metabolic inhibitor SKF-525A significantly decreased the amounts of the volatile metabolites 2-chloro-1,1,1-trifluoroethane and 2-chloro-1,1-difluoroethylene. SKF-525A also decreased the incidence and severity of hepatic damage. Both halothane (1%) and isoflurane (1.1%) anesthesia caused similar reductions in mean arterial blood pressure. However, in contrast to halothane, isoflurane was not hepatotoxic. The results indicate that liver necrosis is unlikely to be caused by anesthesia per se, but rather by hepatotoxic metabolites of halothane. This model offers the opportunity to study the pathogenesis of halothane hepatotoxicity after the administration of halothane alone.

Animals↗
PubMed1983

Inverse relationship of serum LDL cholesterol and the LDL/HDL cholesterol ratio to liver microsomal enzyme induction in man.

The association of serum LDL cholesterol and the LDL/HDL cholesterol ratio, the major positive risk factors of coronary heart disease, to hepatic microsomal enzyme induction assessed by liver cytochrome P-450, was investigated in 18 subjects who were treated with inducing anticonvulsants. In subjects with normal liver histology, LDL cholesterol and the LDL/HDL cholesterol ratio were inversely proportional to the magnitude of induction. Strong induction was associated with a low LDL cholesterol level. The serum cholesterol distribution profile and the low LDL/HDL cholesterol ratio associated with induction are characteristic of low risk of coronary heart disease. The present findings support studies showing a positive association between HDL cholesterol and induction and suggesting a new therapeutic approach to atherosclerotic vascular disease.

Adult↗
PubMed1998

Time course of enzyme induction in liver and kidneys and absorption, distribution and elimination of 1,4-dichlorobenzene in rats.

Time course of enzyme induction was measured in Fischer344 rats treated daily at 150 and 600 mg 1,4-dichlorobenzene (1.4-DCB)/kg p.o. up to 28 days. The monoxygenases 7-ethoxycoumarin O-deethylase (ECOD), 7-ethoxyresorufin O-deethylase (EROD) and aldrin epoxidase (ALD) as well as the phase II enzymes; epoxide hydrolase (EH), glutathione S-transferase (GS-T) and glucuronyl transferase (GLU-T) were dose-dependently induced in the liver of males and females. A pronounced induction in the kidneys was measured at 600 mg/kg only for ECOD. After single oral administration of 100 and 1000 mg/kg bw and feeding of 100 and 1000 ppm (corresponding to approximately 10 and 100 mg/kg bw) to male Wistar rats for 28 days, the time course of 1,4-DCB and 2,5-DCP concentrations was investigated in plasma, adipose, hepatic and renal tissue. In addition, total urinary excretion of 2,5-DCP was determined. After single application, 1,4-DCB and 2,5-DCP were rapidly eliminated from the plasma and tissues, 40-60% of the dose administered was excreted as 2,5-DCP in the urine. There were no indications of cumulative effects after a feeding period of 28 days. The concentrations decreased in all tissues until the 7th day of study. Thereafter, there seems to be a steady state until the 28th day. A total of 7 days after the end of exposure, no more residues could be detected. Following long-term inhalation (450 and 3000 mg/m3) 1,4-DCB concentrations were highest in adipose tissues at 6 months followed by a marked decline at 18 months. 1,4-DCB and 2,5-DCP concentrations in plasma and liver were much lower but again with a peak at 6 months. When compared with published human data on measurements in plasma, urine, liver and adipose tissue the results suggest that there should be no hazard for the general population.

Absorption↗
PubMed1991

Chemoprotective and hepatic enzyme induction properties of indole and indenoindole antioxidants in rats.

Three indole antioxidants were compared for their efficacy to inhibit lipid peroxidation, prevent chemical hepatotoxicity and induce enzyme systems involved in the biotransformation of xenobiotics. The dietary indolyl compound indole-3-carbinol (I-3-C), and the synthetic compounds 5,10-dihydroindeno[1,2-b]-indole (DHII) and 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII) inhibited carbon tetrachloride (CCl4)-initiated lipid peroxidation in rat-liver microsomes, with the order of efficacy THII greater than DHII = butylated hydroxytoluene (BHT) much greater than I-3-C. Each of the indole compounds protected isolated rat hepatocytes against toxicity by CCl4, N-methyl-N'-nitro-N-nitrosoguanidine and methylmethanesulphonate (THII congruent to DHII much greater than I-3-C). In vivo administration of the indole compounds 1 hr before treatment with CCl4 protected against hepatotoxicity (THII greater than DHII greater than I-3-C). For the enzyme induction studies, phenobarbital and beta-naphthoflavone were used as standards, with corn-oil vehicle controls. The compounds were administered by gavage at 50 mg/kg body weight/day for 10 days. I-3-C produced increases in levels of hepatic cytochromes P-450 and ethoxyresorufin O-deethylase (EROD) activity, as well as in UDP-glucuronosyl transferase (UDPGT), glutathione S-transferase (GST), glutathione reductase (GSSG-Red) and quinone reductase. I-3-C produced decreased glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. DHII produced increases in EROD, UDPGT, GST, GSSG-Red and quinone reductase, with decreases in NDMA-demethylase and GSH-Px activities. The only observed effect of THII was a modest induction of EROD activity. After treatment with the indole compounds for 10 days, I-3-C enhanced, while DHII diminished, CCl4-mediated 24-hr hepatotoxicity in rats. We conclude that DHII and THII are suitable candidates to develop further as potential chemoprotective and therapeutic agents for use in humans to treat disorders involving free radicals. THII has the greater radical scavenging efficacy, whereas DHII has the greater capacity to induce many different antioxidative enzymes.

Administration, Oral↗
PubMedDate not supplied

[Age-related changes in cell content (DNA) and glycosaminoglycan-degrading enzymes (beta-glucuronidase, beta-N-acetylglucosaminidase of connective tissue and parenchymal organs of the rat caused by 6-methylprednisolone (enzyme induction, adaptation, acceleration of maturation and possible modification of aging].

This paper is based on previous investigations, which had shown an evident acceleration of maturation and enzyme induction in several organs, not only in the lung, due to a pre- and postnatal application of prednisolone. Applying the same dosage we now investigated whether there is a similar effect of a short-term application of prednisolone in mesenchymal and parenchymal organs of young adult and presenile rats of the same strain (Chbb: THOM/SPF) analyzing the physiological cell regeneration (DNA concentration) as well as functional parameters of the glycosaminoglycan metabolism (e.g. the lysosomal enzymes beta-glucuronidase and beta-N-acetylglucosaminidase). The results show a significant age-dependent decrease of the DNA concentration (lung, spleen, skin, and rib cartilage), a significant age-dependent decrease of the total activity of the beta-glucuronidase (kidney, rib cartilage, and skin) or a significant age-dependent increase of this enzyme activity (spleen and liver) respectively as well as a significant decrease of the beta-N-acetylglucosaminidase activity (skin and rib cartilage) or a significant increase of this enzyme activity (spleen and lung). After application of prednisolone the rats showed a significant reduction of the DNA concentration only in the skin of young adult rats, but no changes in the other organs of the young adult or presenile animals compared to untreated controls. Similar to our findings after postnatal prednisolone application, we found the greatest increases or decreases respectively of the activities of these lysosomal enzymes due to 2- to 3-fold or 4- to 5-fold prednisolone application. Again similar to our previous findings, we found the phenomena of adaptation and rebound effects including the so-called over-compensation in the young adult and especially in the presenile rats but these effects were delayed and weaker in most of the older animals compared to the young adult rats.

Acetylglucosaminidase↗
PubMed1984

Phase II enzyme induction reduces body burden of heptachlor in rats.

Contrary to expectations hexadecane had no significant effect on the body clearance of heptachlor in rats. However, phase II enzyme induction altered the kinetics of heptachlor dramatically, reducing its half-life by about 3-fold. The reduction of half-life was reflected in correspondingly lowered adipose tissue and blood levels.

Alkanes↗
PubMed1981

Effects of microsomal enzyme induction on paracetamol metabolism in man.

1 The metabolism of paracetamol after a single oral dose of 20 mg/kg was compared in fifteen patients with microsomal enzyme induction taking anticonvulsants or rifampicin and twelve healthy volunteers. 2 Induction was confirmed by measurement of the plasma antipyrine half-life (mean 6.4 h in the patients compared with 12.8 h in the volunteers). 3 The glucuronide conjugation of paracetamol was enhanced in the induced patients as shown by lower plasma paracetamol concentrations, a shorter paracetamol half-life, higher paracetamol glucuronide concentrations and an increased ratio of the area under the plasma concentration time curves of the glucuronide to the unchanged drug. There were no significant differences in sulphate conjugation. 4 There was a corresponding change in the pattern of urinary metabolite excretion. The induced patients excreted significantly less unchanged drug and sulphate conjugate and more glucuronide conjugate than the healthy volunteers. 5 The urinary excretion of the mercapturic acid and cysteine conjugated of paracetamol was the same in both groups. 6 Conversion of paracetamol to its potentially hepatotoxic metabolite does not seem to be increased in patients induced with anticonvulsants or rifampicin. There would seem to be no contraindication to the use of these drugs in combination.

Acetaminophen↗
PubMed1977

Alpha-amanitin administration results in a temporary inhibition of hepatic enzyme induction by triiodothyronine: further evidence favoring a long-lived mediator of thyroid hormone action.

Alpha-amanitin was shown to inhibit triiodothyronine (T3)-induced increases in mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) and cytoplasmic malic enzyme activity in the livers of male Sprague-Dawley rats. A 3-fold increase in alpha-GPD observed 24 h after the iv injection of 3 microngT3/100 g BW was completely inhibited by administration of alpha-amanitin at 0 and 8 h. Similarly, alpha-amanitin blocked a two- to four-fold increase in malic enzyme 24 h following iv injection of 3 mg T3/100 g BW into euthyroid rats. After the initial inhibition of enzyme induction by alpha-amanitin was dissipated, however, a delayed but striking increase in enzyme activity occurred. In hypothyroid animals, alpha-GPD activity rose after the initial 24 h inhibition and reached levels at 72 h equal to those observed in hypothyroid rats treated with T3 only. In euthyroid animals treated with T3 and alpha-amanitin, a delayed increase in malic enzyme activity was observed at 72 h and attained values at 96 h similar to those in euthyroid animals injected with T3 only. The delayed rise in enzyme response is most easily explained by the formation of a long-lived intermediate during the exposure of the nuclear sites to T3.

Amanitins↗
PubMed1976

[Gilbert's jaundice. Current clinico-nosographical, physiopathological and therapeutic aspects. Note II. The phenomenon of enzyme induction at the level of the liver].

After a brief survey of the various modifications that may be encountered by drugs through the work of systems that detoxify the liver cell, attention is given to the problem of enzymic induction. The latter is the result of derepression of a gene that codes for a given enzyme; at the molecular level, derepression takes place when the substrate, by changing the tertiary structure of the repressor, brings about its detachment from DNA: in this way, RNA-polymerase is made capable of synthesising the corresponding mRNA. The inducing activity of phenobarbitone, a drug employed classically in the management of Gilbertian forms, must be substantially attributed to an increase in the synthesis of microsomial proteins, as shown by studies with labelled amino acids.

Amino Acids↗
PubMed1988

Contribution of methylsulfonyl metabolites of m-dichlorobenzene to the heme metabolic enzyme induction by the parent compound in rat liver.

In the present study, we investigated the contribution of methylsulfonyl metabolites derived from m-dichlorobenzene (m-DCB) on the heme metabolic enzyme induction by the parent compound in rats. The time courses of the effects of a single ip administration of m-DCB (200 mg/kg, 1.36 mmol/kg) and 2,4- and 3,5-dichlorophenyl methyl sulfones (2,4- and 3,5-DCPSO2Mes) (each 50 mumol/kg) on hepatic microsomal cytochrome P450 content were almost in parallel with those on the total heme content in liver microsomes. m-DCB significantly increased the heme oxygenase activity, but 2,4- and 3,5-DCPSO2Mes did not. On the other hand, m-DCB and both methyl sulfones markedly enhanced the delta-aminolevulinic acid (ALA) synthetase activity. No change was observed in percentage saturation of the tryptophan pyrrolase activity after administration of m-DCB, whereas this ratio at 6 hr after injection of 3,5-DCPSO2Me was increased. In the liver of the DL-buthionine-(S,R)-sulfoximine (BSO)-treated rats dosed with m-DCB, both of 2,4- and 3,5-DCPSO2Mes were present at significantly lower concentrations than in non-BSO-treated rats. Additionally, the m-DCB did not elevate the ALA synthetase activity in the BSO-treated rat. On the other hand, the administration of either 2,4- or 3,5-DCPSO2Mes to BSO-treated rats resulted in induction of ALA synthetase. m-DCB and 2,4- and 3,5-DCPSO2Mes produced a dose-related increase in liver levels of methyl sulfones. The changes in the ALA synthetase activity after the administration of varying doses of m-DCB were similar to those after the administration of 2,4- or 3,5-DCPSO2Mes, whereas the sum of the concentration of two methyl sulfones in the liver of rats dosed with m-DCB was almost the same as the concentration of methyl sulfone after the administration of either 2,4- or 3,5-DCPSO2Mes. The results strongly suggest that the methyl sulfones derived from m-DCB, i.e., 2,4- and 3,5-DCPSO2Mes, contribute highly to the induction of the ALA synthetase activity by the parent compound.

5-Aminolevulinate Synthetase↗
PubMed1976

Effects of toxaphene on hepatic enzyme induction and circulating steroid levels in the rat.

Rats were given a single dose of toxaphene (120 mg/kg, equivalent to 1/2 LD50) and sacrificed at 1, 5, and 15 days. Liver weight and hepatic microsomal enzyme activity were increased at day 5 and 15. The level of plasma testosterone was significantly decreased at day 15. In a second experiment rats were given 2.4 mg/kg daily and sacrificed at 1, 3 and 6 months. Liver weight and microsomal enzyme activity were significantly increased over controls; enzyme activity was, however, decreasing by the end of the experiment. Plasma testosterone levels were not affected. It is concluded that enhanced hepatic enzyme induction causes only a transient drop in circulating testosterone levels followed by a return to normal values.

Animals↗
PubMed2003

Assessment of enzyme induction and aerenchyma formation as mechanisms for flooding tolerance in Trifolium subterraneum 'Park'.

The objective of this study was to evaluate the role of enzyme induction and aerenchyma formation in prolonged tolerance to soil flooding in a variety of underground clover (Trifolium subterraneum 'Park') previously selected for resistance. Seedlings were grown in hydroponic tanks, initially with aeration for 3 weeks and subsequently in the absence of aeration for up to 3 weeks. After 1 h in the absence of aeration, the oxygen concentration in the hydroponic medium had decreased to 1.5 %. During the 3 weeks of extreme oxygen deficiency, primary roots died and were replaced by considerable numbers of adventitious roots. Activities of many glycolytic and fermentative enzymes increased in adventitious roots. Excised adventitious roots were capable of immediate induction of ethanol in the absence of lactate production, in association with energy charge higher than that in excised roots of aerobically maintained controls. Energy charge was even higher when measured in adventitious roots in planta. Interestingly, haemoglobin protein could be correlated with energy charge. Aerenchyma was readily visualized in adventitious roots by optical microscopy of longitudinal and transverse sections. We conclude that avoidance of root anoxia via aerenchyma is the major mechanism for prolonged root tolerance in Trifolium subterraneum 'Park'.

Adaptation, Physiological↗
PubMed1981

Enzyme induction and hepatic glycerolipid synthesis in rats treated with 3-methylcholanthrene.

Fasting male rats fed 3-methylcholanthrene in a daily dose of 40 mg . kg body weight-1 gave evidence of hepatic microsomal enzyme induction after 3 days through significantly increased hepatic aryl hydrocarbon hydroxylase activity, cytochrome P448 content, and characteristic changes in microsomal proteins analysed by sodium dodecyl sulfate--polyacrylamide gel electrophoresis. Concomitantly, activities of aminopyrine N-demethylase and microsomal gamma-glutamyltransferase, which are increased in phenobarbital-treated rats, significantly declined. In contrast to phenobarbital, which has been previously shown to increase hepatic triacylglycerol content and in vitro glycerolipid synthesis, 3-methylcholanthrene did not affect hepatic triacylglycerol content, but did inhibit glycerolipid synthesis by cell-free preparations of rat liver and significantly reduced serum triacylglycerol concentration. Thus, the two prototypical drugs inducing characteristically different changes in microsomal enzyme and hemoprotein response also seem to differ in their effect upon another important microsomal function, hepatic glycerolipid synthesis.

Animals↗