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At least 19 recordsLinked to original sources
PubMed1990

Assessment of enzyme induction and enzyme inhibition in humans: toxicological implications.

1. The principal methods used for the assessment of enzyme induction and enzyme inhibition are measurement of the pharmacokinetics of a model compound (probe drug), analysis of drug metabolism in vitro, and determination of changes in the disposition of, and endogenous substrate for, the enzyme of interest. 2. Probe drugs that have been used for this purpose include antipyrine, aminopyrine, tolbutamide, caffeine, theophylline, warfarin, oxazepam and paracetamol. Measurement of the excretion of metabolites of cortisol and oestradiol, which are endogenous substrates for cytochrome P450 IIIA enzymes, provides a non-invasive means of assessing enzyme induction or inhibition. 3. Combined pharmacokinetic/pharmacodynamic studies are required to assess the pharmacological relevance of either induction or inhibition of the enzymes involved in drug metabolism. 4. At present it is difficult to assess the toxicological implications of enzyme induction and inhibition in man. Safe probe drugs are required for the enzymes primarily responsible for drug detoxication, such as epoxide hydrolase and glutathione transferase, in order to identify individuals particularly at risk.

Biotransformation↗
PubMed1987

Effects of aging on contributions of dietary fat and triiodothyronine treatment to lipogenic enzyme induction.

Although lipogenic enzyme inductions are reduced by fat feeding, this reduction decreases with aging and is particularly detectable in the case of acetyl-CoA carboxylase and fatty acid synthetase activities. On the other hand, the fat-dependent reductions of malic enzyme and acetyl-CoA carboxylase were consistently relieved by triiodothyronine (T3) treatment. The effects of T3 treatment on these enzyme inductions were greater in 10-month-old rats than in 1-month-old rats, while the carbohydrate-dependent induction and the fat-dependent reduction of the enzymes decreased with aging. In these animals, alterations in malic enzyme mRNA translational activities were roughly in parallel to the enzyme activities. Therefore, the age-dependent alterations in effects of T3 treatment and fat on malic enzyme induction do not appear to occur in post-translation.

Acetyl-CoA Carboxylase↗
PubMed1978

The effects of chronic drug administration on hepatic enzyme induction and folate metabolism.

1 Patients on prolonged treatment with anticonvulsant and phenothiazine drugs exhibited lower than normal concentrations of folate in serum and erythrocytes, and showed increased urinary FIGLU excretion after histidine loading; urinary excretion of D-glucaric acid was also increased suggesting induction of the hepatic microsomal enzymes. 2 Folate deficiency by enzyme-inducing drugs was seen to be determined more by the duration of therapy than by the nature of the drugs. Excretion of FIGLU was increased by 70% by 2-5 years of treatment with anticonvulsant, phenothiazine or tricyclic drugs, and by 200% after 6 or more years. 3 Hepatic microsomal enzyme induction, as measured by D-glucaric acid excretion, was greatest after 2-5 years treatment. 4 It is suggested that the increased requirements for folate, resulting from microsomal enzyme induction, lead to folate deficiency and this subsequently limits enzyme induction, leading to adverse drug side-affects. 5 The dietary folate of hospitalized patients would seem to be generally inadequate for patients on long term treatment with enzyme-inducing drugs.

Adult↗
PubMed1992

Enzyme induction by drugs and toxins.

Enzyme induction by drugs mostly concerns those enzymes involved in drug metabolism: cytochromes P-450, UDP-glucuronosyltransferases, glutathione S-transferases, gamma-glutamyltransferases and epoxide hydrolases. A large variety of molecular forms exists, but not all of them are inducible (e.g. the inducible cytochromes P-450 in man are members of family IA, IIA, IIC, IIE, IIIA). Induction is most common in the liver, but also occurs in other organs (lung, placenta, lymphocytes). Over the past 20 years a relatively small number of drugs and environmental chemicals have been identified as enzyme inducers, perhaps fewer than early studies suggested. Information on inducing properties must be obtained as early as possible during the development of a new drug and made available to clinicians and clinical chemists when the drug is marketed. The main consequences of enzyme induction are changes in pharmacokinetics of the drug itself or of an associated drug. Much progress has been made in methods to identify these inducers.

Animals↗
PubMed1989

Urinary excretion of 6 beta-hydroxycortisol and the time course measurement of enzyme induction in man.

The effect of enzyme induction by antipyrine, phenobarbitone and rifampicin on the time-course of urinary 6 beta-hydroxycortisol (6 beta-OHC) excretion was investigated in healthy volunteers. The drugs were given chronically for either seven or 14 days. Significant increases in 6 beta-OHC excretion were observed after 4 days administration of antipyrine (1.2 g), 13 days administration of phenobarbitone (100 mg), and only 2 days administration of rifampicin (0.6 or 1.2 g). During 14 days rifampicin administration (1.2 g) 6 beta-OHC excretion, for individual subjects, reached a maximum on Days 11-14 when excretion was significantly greater than on day 7. On stopping rifampicin, in a 7-day study, excretion decreased over the next six days, but still remained significantly elevated compared to the original control values. These studies show that measurement of urinary 6 beta-hydroxycortisol provides a simple non-invasive method with which to monitor the time-course of enzyme induction by drugs in man. However, the method cannot be used to predict clinically important drug interactions until the cytochrome P-450 enzyme responsible for cortisol 6 beta-hydroxylation has been fully characterized.

Adult↗
PubMed1975

Colchicine effects on lysosomal enzyme induction and intracellular degradation in the cultivated macrophage.

The effects of colchicine on lysosomal fusion and lysosomal enzyme induction in the cultivated mouse peritoneal macrophage have been examined. Colchicine (10- minus 6 M), but not lumicolchicine, inhibited lysosomal enzyme induction by both phagocytic and pinocytic stimuli. In addition, the drug significantly retarded pinocytic uptake of [3-H] sucrose and transport of the amino acids [3-H] alpha aminoisobutyric acid and L-[3-H] leucine. In contrast, lumicolchicine had no effect on pinocytosis or amino acid transport. Thus, a role for intact microtubules in lysosomal enzyme induction, pinocytosis, and amino acid uptake in these cells is suggested. That colchicine inhibited lysosomal enzyme induction by phagocytic stimuli under conditions in which pinocytosis contributed little to the enzyme rise indicated that inhibition of pinocytosis was unlikely to account for colchicine effects on lysosomal enzyme induction. Effects of colchicine on degradation of phagocytized and pinocytized substrates were examined to determine if intact microtubules are required for fusion among lysosomes, pinosomes, and phagosomes. Colchicine did not alter the rate of intracellular digestion of radiolabeled bacteria by the cultivated macrophage. Similarly, it had no effect on enzymatic hydrolysis of intracellular [3-H] sucrose resulting from uptake of exogenous invertase. The finding that colchicine had no effect on the functional consequences of fusion of lysosomes with endosomes suggests that intact microtubules are not required for fusion among these constituents of the vacuolar apparatus.

Acid Phosphatase↗
PubMed1990

Enzyme induction and inhibition.

The rate and extent of drug metabolism significantly influences drug effect. Enzyme induction by increasing the metabolism of drugs may result in important drug interactions. Other implications of enzyme induction include alterations in the metabolism of endogenous substrates, vitamins and activity of extrahepatic enzyme systems. Similarly a wide range of drugs may produce clinically significant drug interactions following enzyme inhibition. Assessment of enzyme induction and inhibition in man involves diverse methods including the use of model drugs.

Enzyme Induction↗
PubMed1985

[Metabolic aspects of alcoholic liver damage: 1984/1985 update. 2: Microsomal enzyme induction and hypermetabolism].

In the second part of this review, the effect of ethanol on hepatic microsomal enzymes is primarily discussed. Since ethanol is metabolized via a cytochrome P-450 dependent biotransformation system (MEOS) in hepatic microsomes, the microsomal enzyme induction in the smooth endoplasmic reticulum has to be considered as an adaptive response. This enzyme induction results in an accelerated metabolism of ethanol. However, subsequently, the negative consequences of such a microsomal enzyme induction are predominant. Acetaldehyde production increases and oxygen consumption is enhanced leading to pericentral (perivenular) hypoxia. In addition, microsomal enzyme induction results in an enhanced metabolism of drugs, xenobiotics and hepatotoxins and thus to an increased production of toxic intermediates. Also procarcinogens are activated to a higher degree in microsomes following chronic ethanol consumption. Subsequently, an enhanced microsomal metabolism of vitamin A may explain the low serum concentrations of this vitamin in the alcoholic and may lead to toxic metabolites of retinol. The quantitative role of an enhanced reoxidation of NADH responsible for an increased oxidation of alcohol following chronic ethanol ingestion has still to be determined. However, according to recent investigations, a thyroid hormone induced hypermetabolism seems unlikely.

Acetaldehyde↗
PubMed1986

The effect of low-dose phenobarbitone on three indices of hepatic microsomal enzyme induction.

The effects of low-dose phenobarbitone on three indices of hepatic enzyme induction were studied. Eight healthy volunteers took phenobarbitone 7.5 mg daily for 4 weeks followed by 15 mg daily for 4 weeks; five subjects took 30 mg daily for a further 2 weeks. Phenobarbitone 15 mg daily produced a significant rise in antipyrine clearance (P less than 0.05). Phenobarbitone 30 mg daily produced a further rise, but probably because of the reduced numbers of subjects, this did not achieve significance (P = 0.06). Urinary 6-beta-hydroxycortisol and D-glucaric acid levels did not change significantly and remained within the range seen in subjects not taking enzyme-inducing drugs. We conclude that phenobarbitone 7.5 mg daily produces little (if any) enzyme induction whereas 15 mg, or more, may have the potential to produce drug interactions through enzyme induction.

Adult↗
PubMed1991

Swedish dioxin survey: evaluation of the H-4-II E bioassay for screening environmental samples for dioxin-like enzyme induction.

The H-4-II E enzyme induction bioassay was used for testing both pure reference substances and extracts of wildlife samples. Polychlorinated naphthalenes were found to be as active as enzyme inducers as certain coplanar polychlorinated biphenyls (PCBs). Also a mixture of polybrominated diphenyl ethers (Bromkal 70-5DE) was shown to induce enzyme activity. In extracts of herring, containing polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), bioassay and chemically derived TCDD-equivalents (TEQs) were nearly identical. When extracts containing other types of dioxin-like compounds as well were tested, the bioassay TEQs for most of them agreed well with chemical TEQs calculated for PCDDs, PCDFs and non-ortho PCBs. However, for ringed seal and whitefish, TEQs obtained from the bioassay were higher than those from the chemical analysis. Our results indicate that this bioassay is an excellent complement to chemical residue analysis and a useful tool in understanding the complex interactions of halogenated hydrocarbons. For risk assessment, such results should, however, be used most carefully as they are measured in vitro.

Animals↗
PubMed1987

Pharmacokinetics of chlorpropamide in epileptic patients: effects of enzyme induction and urine pH on chlorpropamide elimination.

The effects of liver enzyme induction and of urine pH on the pharmacokinetics of chlorpropamide have been studied. A single oral dose of chlorpropamide 250 mg was administered to 8 patients on antiepileptic drugs (phenytoin, carbamazepine) and to 8 healthy volunteers. The half-life of chlorpropamide was significantly shorter in the patients (34.4 h) than in the healthy volunteers (50.2 h), but the difference between the groups in the half-life of antipyrine was even more pronounced (5.1 vs 11.4 h). The clearance and volume of distribution of total chlorpropamide were significantly higher in the patients (2.99 ml X h-1 X kg-1 and 126 ml X kg-1) than in the healthy volunteers (1.60 ml X h-1 X kg-1 and 106 ml X kg-1). The unbound fraction of chlorpropamide in serum was also higher in the patients (5.7%) than in the healthy subjects (4.4%). Neither the volume of distribution nor the clearance of the free fraction of chlorpropamide differed significantly between the groups. There was a significant correlation between the half-lives of chlorpropamide and antipyrine, and the half-life of chlorpropamide also had at least as good an inverse correlation with the urinary excretion of unchanged chlorpropamide. The renal clearance of chlorpropamide correlated well with urine pH and was almost 100-fold higher at pH 7 than at pH 5. Both the metabolic and renal clearances of chlorpropamide are important in its elimination. At urine pH higher than 6.5-7, the renal clearance of chlorpropamide represents more than half its total clearance regardless the degree of induction of liver enzymes.

Adult↗