Enzyme induction and modulation.
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A model for the mechanism of enzyme induction.
A sequence of reactions is postulated from which are derived equations describing the time course of enzyme induction. The model also yields the observed effect of the inducer concentration on the time constant and final rate of enzyme synthesis. Features of the model are: (a) The inducer acts first to release the protein forming template from its site of synthesis on the gene. (b) The inducer is involved again in the equilibrium dissociation of the free template-inducer complex which is utilized in the synthesis of the enzyme-forming unit. (c) The final enzyme-forming unit is unstable and must be synthesized continuously to maintain enzyme synthesis.
Enzyme Induction↗
Heavy metals and enzyme induction.
In experiments on male albino rats it was established that single toxic doses of heavy metal salts inhibited to a different extent the enzyme-inducing action of phenobarbital and methylcholanthrene as determined by ethylmorphine-N-demethylase, respectively aniline hydroxylase activity. The majority of salts (of Cu, Co, Cd, Pb, Ni, Zn and Hg) inhibited more strongly the enzyme induction produced by methylcholanthrene as compared with that caused by phenobarbital. Subtoxic doses of Co, Cd, Zn and Ni salts given daily with the drinking water for 30 days shortened the hexobarbital sleeping time and increased the ethylmorphine-N-demethylase activity and cytochrome P-450 content in the liver microsomes. This suggests an enzyme-inducing action of these heavy metal salts at oral administration in subtoxic doses. Cu, Bi, Sn, Pb did not produce enzyme induction. The changes in the three indices of the As and Hg action were not consistent in our experiments.
Animals↗
The relationship among microsomal enzyme induction, liver weight, and histological change in cynomolgus monkey toxicology studies.
The purpose of this investigation was to examine the relationship among hepatic microsomal enzyme induction, liver weight, histological evidence of hepatic injury, and serum clinical chemistry markers of hepatic origin in the cynomolgus monkey. We report here the results from independent toxicology studies for 10 investigative drug candidates representing four therapeutic classes. Study conditions were selected to elicit target organ toxicity. We found that six of the 10 compounds altered cytochrome P450-associated activities in both male and female monkeys, two in females only, and one altered similar activities in males only. Frequently, significant treatment-related elevations in NADPH cytochrome c reductase and ethylmorphine N-demethylase were noted. When the results from all 10 studies were pooled, 14 cytochrome P450-associated activities were significantly increased and five were decreased in males compared to 15 significantly increased and three decreased in the females. Treatment-associated liver weight increases were noted in four studies. Except for hepatocellular hypertrophy in one study, no significant treatment-related microscopic changes in liver and no elevations of serum biomarkers commonly associated with liver toxicity were observed in any of the studies that demonstrated significant hepatic enzyme induction. Compared to parallel rat studies, one compound was an inducer only in monkeys and one was an inducer only in rats. Significant elevations of microsomal drug-metabolizing enzymes in the cynomolgus monkey liver are not accompanied by substantial hepatic changes except for hepatomegaly. These alterations in the hepatic drug-metabolizing enzyme system were benign based the absence of histopathological lesions and serum biomarkers of hepatobiliary toxicity.
Animals↗
A review of enzyme induction of warfarin metabolism with recommendations for patient management.
We conducted a review of literature from the MEDLINE data base (1966-January 1997), and bibliographies of published articles, reviews, and letters to classify enzyme induction of warfarin metabolism interactions by onset, extent, and offset. Ten hepatic microsomal enzyme agents were assessed. Likelihood of interaction was based on the strength of supporting literature. Enzyme induction of warfarin metabolism by rifampin and barbiturates is considered likely, although the characteristics of the interactions are different. An interaction is probable with carbamazepine, griseofulvin, aminoglutethimide, nafcillin, and dicloxacillin. A suspected interaction may occur with smoking and long-term alcohol consumption. Ingestion of a small amount of alcohol is unlikely to interact with warfarin. The effect of phenytoin on warfarin metabolism is unpredictable. Anticipation of the expected time course and extent of interaction may allow for better therapeutic decisions and decrease the chance of inappropriate anticoagulation with its potential for complications.
Animals↗
Enzyme induction following surgery with halothane and neurolept anesthesia.
Salivary antipyrine clearance was determined before and 4 or 8 days after surgery as a measure of enzyme induction in 25 patients given halothane anesthesia and in 29 patients given neurolept anesthesia for uncomplicated otic surgical procedures. Statistically significant but clinically small increases in antipyrine clearance of 20% and 16% were measured in the halothane and neurolept groups, respectively. Similar decreases in antipyrine half-life were observed; apparent volume of distribution was unchanged. These changes are interpreted as representing a clinically insignificant degree of enzyme induction in most patients. The cause of these changes is not readily apparent. They may be due to the administration of anesthetic and adjuvant drugs, to the stress associated with the entire surgical experience, or to a combination of these factors.
Adult↗
Cytochrome P450 mRNA expression in peripheral blood lymphocytes as a predictor of enzyme induction.
OBJECTIVE: Previous reports have supported the concept that messenger ribonucleic acid (mRNA) concentrations for cytochrome P450 (CYP) enzymes in peripheral blood mononuclear cells may be predictive of systemic enzyme activity. We investigated whether changes in mRNA expression for CYP1A2,CYP2C19, CYP2D6 and CYP3A4 in peripheral blood lymphocytes (PBLs) may serve as surrogate markers for changes in CYP enzyme activity following the administration of rifampin. METHODS: On day 1 and day 9 of the study, 12 healthy volunteers were administered caffeine 100 mg, debrisoquine 10 mg and omeprazole 40 mg orally, along with midazolam 0.025 mg/kg intravenously. Blood samples and urine were collected for 8 h after drug administration. The subjects took rifampin 300 mg (n = 6) or 600 mg (n = 6) daily on days 2-8. Total RNA was isolated from PBLs on day 1 and day 9, and mRNA expression for the CYP enzymes and hGAPDH were determined by means of quantitative, real-time, reverse-transcriptase polymerase chain reaction. CYP1A2 activity was estimated by calculating the plasma paraxanthine to caffeine AUC ratio (caffeine metabolic ratio; CMR), CYP2C19 activity by the 2-h omeprazole hydroxylation index (HI), CYP2D6 activity by the urinary debrisoquine recovery ratio (DBRR) and CYP3A4 activity by midazolam clearance. RESULTS: Median midazolam clearance (0.362 to 0.740 l/kg/h), omeprazole HI (0.752 to 0.214), CMR (0.365 to 0.450) and DBRR (0.406 to 0.479) all changed significantly following rifampin, consistent with the expected enzyme induction. CYP1A2,CYP2D6 and CYP3A4 mRNA content were measurable in all samples. CYP2C19 mRNA was inconsistently detectable. There were no significant correlations between changes in enzyme activity and mRNA expression by Spearman's rank order correlation. CONCLUSION: The results do not support the use of mRNA expression assays for CYP1A2, CYP2C19, CYP2D6 and CYP3A4 enzymes in PBLs as surrogates for quantifying changes in systemic enzyme activity in the setting of enzyme induction.
Adult↗
An evaluation of the low-pH enzymatic assay of urinary D-glucaric acid, and its use as a marker of enzyme induction in exocrine pancreatic disease.
We have evaluated a low-pH enzymatic method for measuring urinary D-glucaric acid, and its usefulness as a marker of 'enzyme induction' in patients with exocrine pancreatic disease. The coefficient of variation lay between 7.5 and 10.9% for within-batch precision, and between 7.9 and 19.8% for between-batch precision. The useful range of the method was 20-200 mumol/l, with a lower detection limit of 11 mumol/l. The molar concentration ratio of D-glucaric acid to creatinine in urine correlated with the 8-h output of D-glucaric acid (p less than 0.005): both indices were significantly higher in a group of 29 patients with exocrine pancreatic disease than in controls (median ratios 4.6 and 2.9 X 10(-3), p less than 0.005; median outputs 14.0 and 8.8 mumol/8 h, respectively, p less than 0.005). Comparison with the results of theophylline tests in the same group of patients showed that whereas 72% of patients had theophylline clearances higher than the highest value in controls, 45% of the group had increased D-glucaric acid/creatinine ratios, whilst only 21% had increased outputs of D-glucaric acid. Paradoxically, in patients with established liver disease in whom drug metabolism was impaired urinary D-glucaric acid values were amongst the highest encountered in the study. Thus, the obvious advantages of the method--non-invasive, simple, reproducible, inexpensive, easily applied to out-patients--are offset by an unacceptably low predictive value as an indicator of microsomal 'enzyme induction'.
Adult↗
Theoretical aspects of enzyme induction and inhibition leading to the reversal of resistance to biocides.
The well-known phenomena of enzyme induction and inhibition have been applied in the enunciation of two mechanisms which could be used in the reversal of resistance which organisms develop towards biocides (drugs and pesticides) in many cases. For those biocides active per se which are metabolized by inducible enzymes to non-toxic metabolites, resistant organisms would be those possessing high levels of drug-metabolizing enzymes (Mechanism 1). For those biocides inactive per se but requiring metabolic activation for activity, resistant organisms would be those possessing low levels of drug metabolizing enzymes (Mechanism 2). In mechanism 1, the addition of enzyme inhibitors to the biocide would be effective in reversing resistance. In mechanism 2 the addition of an enzyme inducer to the biocide would increase the susceptibility of the resistant organisms. An ectoparasite insecticide 2-chloro-1-(2,4 dichlorophenyl) vinyl diethylphosphate (chlorfenvinphos or supona) is used as an example for mechanism 1. The malarial drugs primaquine and chloroquine are used as examples of mechanism 2.
Adult↗
Computation of the fraction of induced cells in enzyme induction systems.
A theoretical model is developed for continuous multistage enzymed production systems, which consist of a growth fermentor used for growing microorganisms rapidly without enzyme production and a subsequent system of induction reactors in which enzyme induction and production occurs. The model allows the computation of the fraction of induced cells residing in the induction reactors for organisms exhibiting a lag phase in enzyme induction. For this model a general analytical solution was obtained for the cumulative internal residence time distribution of a series of n well-sterred vessels with a recycle. The theoretical results are compared in a preliminary way with experimentally measured cellulase productivities of continuous multistage cellulose fermentations with Trichoderma viride QM 9414.
Cell Division↗
Liver enzyme induction and inhibition: implications for anaesthesia.
Recent breakthroughs in molecular biology have enabled a reclassification of drug metabolising enzymes based on their amino acid sequence. This has led to a better understanding of drug metabolism and drug interactions. The majority of these drug metabolising enzymes may be either induced or inhibited by drugs or by extraneous substances including foodstuffs, cigarette smoke and environmental pollutants. Virtually all drugs used in anaesthesia are metabolised by either hepatic phase 1 or phase II enzymes. This review considers the classification of drug metabolising enzymes, explains the mechanisms of enzyme induction and inhibition, and also considers how the action of drugs commonly used by anaesthetists, including opioids and neuromuscular blocking drugs, may be altered by this mechanism.
Analgesics, Opioid↗
Hepatic microsomal enzyme induction and its evaluation in a clinical laboratory.
We tried to determine whether short-term treatment with alpha-methyldopa, quinidine, digoxin, diazepam or furosemide--drugs in common use in hospitals--is capable of stimulating the activity of hepatic microsomal drug-metabolizing enzymes. Glucaric acid (GA) excretion and serum activity of gamma-glutamyl transpeptidase (GGT) were used as indicators of hepatic microsomal enzyme activity. Increased GA excretion was found in 45% and increased serum GGT activity in 40% of the patients on drug treatment. Only 14.3% showed an increase in both indicators. The excretion of GA rose significantly in patients who received drugs for less than 10 days, as compared with those who received drugs for less than 10 days, whereas the percentage of high GGT values did not rise significantly with increased duration of treatment. The lack of correlation between serum GGT activity and GA excretion casts doubt on the value of GGT as a consistent indicator of microsomal enzyme induction. GA excretion, on the other hand, seems to be a dependable index of microsomal enzyme induction in response to short-term treatment with standard doses of several widely used drugs.
Adult↗
Enzyme induction by ethanol consumption affects the pharmacokinetics of inhaled m-xylene only at high levels of exposure.
The experimental study with rats was undertaken to verify the working hypothesis that enzyme induction caused by ethanol consumption affects the kinetics of m-xylene only at a high level of exposure. m-Xylene was administered to ethanol-treated rats either perorally (0.01, 0.02 or 0.1 ml/kg) or by inhalation (50, 100 or 500 ppm each for 6 h) and the concentration of m-xylene in the blood and the urinary excretion of a m-xylene metabolite (m-methyl hippuric acid or m-MHA) were measured with time. The ethanol consumption, which increased the in vitro m-xylene metabolism about 5-fold, had no effect on the metabolism of inhaled m-xylene in vivo until the exposure concentration was raised to 500 ppm. On the other hand, metabolism of m-xylene after oral administration was markedly enhanced at any dose by the consumption, as evidenced by a decrease in the blood concentration of m-xylene together with an increase in the urinary excretion of m-MHA. These findings indicate that enzyme induction does not affect the pharmacokinetics of inhaled m-xylene when its exposure concentration is low. This may be because the hepatic blood flow, rather than the enzyme activity, rate-limits the metabolism of m-xylene, which is highly metabolized in the liver.
Administration, Inhalation↗
Molecular basis for hepatic detoxifying enzyme induction by 2-(allylthio)pyrazine in rats in comparison with oltipraz: effects on prooxidant production and DNA degradation.
The expression of hepatic microsomal epoxide hydrolase (mEH) and glutathione S-transferases (GSTs) by 2-(allylthio)pyrazine (2-AP), an experimental chemopreventive agent, was investigated in rats. Northern blot analysis revealed that 2-AP caused increases in mEH, rGSTA2/3/5, and rGSTM1/2 mRNA levels. mEH and rGSTA2 proteins were also induced. Molecular basis of the enzyme induction by 2-AP was studied in comparison with oltipraz (Olt). Rats exposed to buthionine sulfoximine, a GSH-depleting agent, before treatment with either 2-AP or Olt exhibited greater increases in the mRNA levels than the individual treatment. Conversely, increases of the mRNAs were prevented by cysteine treatment, indicating that metabolic intermediates or reactive oxygens produced from the agents could be reduced by cysteine. Gel shift analysis revealed that nuclear factor-kappaB, which is associated with the altered cellular redox state, was not activated by the agents. Effects of these agents on the breakage of phix-174 DNA were compared in vitro. 2-AP effectively reduced the conversion of supercoiled DNA to the open circular form induced by benzenetriol and prevented benzenetriol- and iron-catalyzed degradation of DNA, whereas Olt failed to prevent strand breakage of DNA. These results provided evidence that: 1) 2-AP was effective in elevating the hepatic mEH and GST gene expression in rats, which might be mediated with the production of reactive oxygen species; 2) nuclear factor-kappaB activation was not involved in the induction of the detoxifying enzymes by either 2-AP or Olt in spite of their production of reactive oxygens in vivo; and 3) the antioxidant effect of 2-AP in vitro differed from that of Olt.
Animals↗
Urinary D-glucaric acid, a marker substance for microsomal enzyme induction. Methodological aspects, responses to alcohol and findings in workers exposed to toluene.
D-glucaric acid, an end product of glucuronic acid metabolism, has been used as a marker substance for microsomal enzyme induction. In this study a convenient microtitre-plate based method for the quantification of urinary D-glucaric acid has been developed and validated. Mean urinary D-glucaric acid excretion in 20 health humans as measured by this method was 3.2 mumol glucaric acid mmol-1 creatinine, 95% confidence interval 3.0-3.4. Moderate alcohol consumption in 18 healthy volunteers did not significantly augment the urinary D-glucaric acid excretion. Occupational exposition to toluene in a printing plant was investigated. In spite of considerable intra- and inter-individual variability, a significant difference between exposed (3.5, 3.1-3.9) and non-exposed (2.6, 2.2-3.0) workers was observed, p < 0.025. We conclude that the measurement of D-glucaric acid can be utilized for biological screening of enzyme induction on a group basis.
Adult↗
Human response to dioxin: aryl hydrocarbon receptor (AhR) molecular structure, function, and dose-response data for enzyme induction indicate an impaired human AhR.
The aryl hydrocarbon receptor (AhR) mediates nearly all studied adverse effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and many related compounds. Binding of TCDD or related ligands to AhR is the key initiating event in downstream biochemical responses. The binding affinity of AhR for TCDD is specific to species and strain, and studies of human AhR demonstrate binding affinities approximately an order of magnitude or more lower than those observed in the most sensitive laboratory strains and species. Molecular genetic studies confirmed that human AhR shares key mutations with the DBA mouse strain that result in an "impaired" AhR (with respect to TCDD binding and responsiveness). Despite a number of polymorphisms in human AhR, the key "DBA-type" mutations appear to be a constant feature of the human AhR, and no polymorphisms have been identified that compensate for the impaired binding function conferred by these mutations. Consistent with the impaired binding status of the human AhR, human cells have consistently required approximately 10-fold higher concentrations of TCDD in vitro than rodent cells to respond with enzyme induction. Recent studies of in vivo enzyme induction-related endpoints in human populations with moderately and highly increased TCDD body burdens detected no relationship between these endpoints and TCDD body burdens at body-burden levels up to 250 ng TEQ/kg body weight, or approximately 25 times above the upper range of current general population background body burdens, while marked elevations in enzyme activity were observed in persons with body burdens above 750 ng TEQ/kg. In contrast, the more sensitive laboratory rodent strains and species exposed to TCDD exhibit significant enzyme induction at body burdens below 50 ng/kg. These interspecies data on the most sensitive and best understood response to binding of TCDD and related compounds to the AhR are consistent with the binding affinity and molecular structure data and support the hypothesis that the human AhR is less functional than the AhR of the more sensitive laboratory animals at a molecular level. Quantitative risk assessments involving interspecies extrapolation from sensitive laboratory species and strains should take these fundamental differences into account when margins of exposure and safety factors are considered.
Animals↗
Hepatic enzyme induction with phenobarbital and doxorubicin metabolism and myelotoxicity in the rabbit.
Doxorubicin (DOX) undergoes extensive liver metabolism. This study was designed to compare the pharmacokinetic and myelotoxicity profiles of DOX and metabolites with and without phenobarbital-associated hepatic enzyme induction. DOX was administered i.v. to eight rabbits with and without 7 prior days of oral phenobarbital, with venous blood samples collected between 0 and 72 hr for determination of plasma DOX and metabolite concentrations by high-performance liquid chromatography and complete blood counts obtained on days 1, 5, 7, 8, and 9. DOX AUC infinity, t1/2 beta and CLT values were significantly reduced by phenobarbital induction (PBI), while only the formation clearance of DOX metabolites was significantly changed. PBI had no effect on nadir neutrophil counts but was associated with significantly accelerated neutrophil recovery. Hepatic enzyme induction with phenobarbital significantly reduces plasma DOX exposure while increasing the rate of metabolite formation. These effects result in significant acceleration of neutrophil recovery.
Animals↗
Thyroid and liver trophic changes in rats secondary to liver microsomal enzyme induction caused by an experimental leukotriene antagonist (L-649,923).
Thyroid hyperplasia and/or hepatomegaly were observed in a 14-week oral toxicity study with L-649,923, a leukotriene antagonist, at doses of 50 and 150 mg/kg/day. In a 16-day study, L-649,923 caused an increase in plasma TSH and hepatic enzyme induction, but did not affect plasma T3 and T4 levels. Light microscopy and ultrastructural examination of the liver and thyroid showed changes indicative of hepatic enzyme induction and increased stimulation of the thyroid by TSH. Because other hepatic enzyme inducers cause thyroid hyperplasia by increasing the turnover of plasma T3 and T4 it was hypothesized that L-649,923-induced thyroid hyperplasia might be occurring by the same mechanism. To examine this theory, rats were treated po with 300 mg/kg/day of L-649,923 for 17 days. On Day 15, all rats were dosed iv with [125I]thyroxine (33 microCi/rat). At various times after dosing, blood was collected and plasma levels of 125I were determined. The clearance and elimination rate constant were significantly larger in treated animals than in the control group (p less than 0.01). This work demonstrates that L-649,923 increases the plasma turnover of thyroxine which is associated with a stimulation of TSH and thyroid hyperplasia.
Animals↗