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PubMed1980

Development and regression of the hepatic microsomal enzyme induction and stimulation of biliary excretion produced by phenobarbital in rats.

The time-course effect of a single dose (75 mg/kg i.p.) of phenobarbital (PB) and that of prolonged PB treatment (75 mg/kg daily i.p., for 1 to 5 days) on the hepatic excretory and microsomal enzyme functions have been studied in rats. PB given in a single dose resulted in hypercholeresis 6 hr, an increase in the biliary excretion rate of bromcresol green and in hepatic cytochrome P-45 concentration 12 hr, and shortening of hexobarbital sleeping time 24 hr after the administration. All these changes, except the hypercholeresis, became gradually more apparent following the repeated daily administration of PB. Regression of the changes was faster in biliary excretory function than in microsomal function. Biliary flow and biliary output of bromcresol green returned to the control level at 72 hr after a single dose of PB or at 5 days after the cessation of a 5-day PB treatment, whereas enzyme induction was still apparent at those times. These results indicate that no close correlation in time exists between PB produced hepatic microsomal enzyme induction and the stimulatory effect of PB on biliary excretion.

Animals↗
PubMedDate not supplied

Effects of microsomal enzyme induction on the toxicity of pyrrolizidine (Senecio) alkaloids.

Effects of microsomal enzyme induction by phenobarbital (PB) injection (ip) and ingestion of Eucalyptus globulus foliage or phenothiazine (PT) on the toxicity of pyrrolizidine alkaloids (PA) or dried plant material of Senecio longilobus (SL) and Senecio jacobaea (SJ) were evaluated in rats. The oral median lethal doses (LD50) for a PA mixture extracted from SL at 72, 144, and 168 h post PA administration were approximately greater than 320, 190, and 160 mg/kg, respectively. Induction of mixed-function oxidase (MFO) activity by PB or dietary eucalyptus leaves resulted in only a marginal effect on the acute LD50, with no effective change at 168 h. The LD50 values at 72, 144, and 168 h for PB-treated rats were approximately 320, 190, and 160 mg/kg, and for eucalyptus treated rats approximately 127, 133, and 133 mg/kg, respectively. Dietary PT did not alter the toxicity of SJ but did cause reductions in feed intake and average daily gain. Supplemental cysteine increased (p less than 0.05) survival time in SJ-consuming rats, with a concomitant increase (p less than 0.05) in SJ ingestion, and caused slight increases in average daily gain. The simultaneous addition of cysteine and PT to an SJ-containing diet resulted in an increased (p less than 0.05) survival time over SJ and SJ + PT diet groups and a slight decrease in survival time compared to the SJ + cysteine group.

Animals↗
PubMed1980

[Medicamentous enzyme induction and hormonal contraception. First communication: effects of anti-epileptics on hormonal contraception of epileptics (author's transl)].

Studies were conducted into the effects of anti-epileptics on hormonal contraception of epileptics, with reference being primarily made to biochemical as well as clinicoexperimental findings regarding medication and its effects, through the mechanism of medicamentous enzyme induction, on biological transformation of steroid hormones. Disorders of bleeding, the most sensitive symptom of enzyme induction, occurred more often than they did in a control group, the difference in occurrence being secured with significance. Contraceptive protection of those patients was equally reduced. Conclusions were drawn for contraceptive practice.

Adult↗
PubMed1980

[Medicamentous enzyme induction and hormonal contraception. Second communication: effects of phenobarbital and phenylbutazone on hormonal contraception (author's transl)].

The effects of phenobarbital and phenylbutazone on hormonal contraception of clinically intact women were studied for the purpose of obtaining information on consequences of medicamentous enzyme induction. Disorders of bleeding were evaluated from four groups of probands who had received complementary doses of phenobarbital or phenylbutazone along with hormonal contraception, and findings were compared with data obtained from a control group. Occurrence of medicamentous enzyme induction was clinically reflected in an accumulation of functional bleeding disorders, depending on the hormonal contraceptive used as well as on the additionally administered drug. Conclusions were drawn for contraceptive practice.

Adult↗
PubMed1981

Coronary heart disease, cancer, lipoproteins, and the effects of clofibrate: is enzyme induction a common link and are lipoproteins red herrings?

Inverse correlations between coronary heart disease (CHD) and cancer linked to circulatory levels of total and high density lipoprotein (HDL) cholesterol have been observed. This pattern (low total cholesterol/high HDL cholesterol/high cancer/low CHD) is largely mimicked by the effects of clofibrate. Clofibrate may act as an enzyme inducer and the hypothesis is that enzyme induction is responsible for this pattern. The associations between lipoproteins and both CHD and cancer may be spurious, and enzyme induction may be causally related to all the features of the pattern of correlations.

Carcinogens↗
PubMed1983

Inhibition by sodium butyrate of enzyme induction by glucocorticoids and dibutyryl cyclic AMP. A role for the rapid form of histone acetylation.

We have found that butyrate selectively inhibits hormonal induction of a few specific proteins and messenger RNAs in hepatoma cells. The fatty acid salt reversibly abolishes induction of tyrosine aminotransferase by dexamethasone and dibutyryl cyclic AMP in HTC cells by inhibiting the production of tyrosine aminotransferase messenger RNA. Half-maximal inhibition of enzyme induction occurred in 0.9 mM butyrate. This effect is highly specific, since 4 h after the addition of butyrate to induced HTC cells, the relative abundance of only five messenger RNA species out of several hundred observable on two-dimensional gels of translational products is changed. Upon removal of the butyrate from cell cultures pretreated with dexamethasone, tyrosine aminotransferase activity begins to increase more rapidly than if dexamethasone is added to control cultures, indicating that part of the induction process occurs in the presence of butyrate. A dose-dependent reduction of fast histone acetylation by butyrate was demonstrated by treating cells with butyrate followed by a short pulse with [3H]acetate and chase in a high concentration of butyrate. The butyrate concentration test range over which rapid histone acetylation is inhibited is similar to that which inhibits enzyme induction to the same extent. In contrast, the slow form of histone acetylation is unaffected in the concentration range examined. The induction of tyrosine aminotransferase by dexamethasone is delayed in hypoacetylated cells. This lag is consistent with the time required to initiate the recovery of the fast form of histone acetylation after its transient disappearance (Covault, J., Perry, M., and Chalkley, R. (1982) J. Biol. Chem. 257, 13433-13440). We conclude that sodium butyrate interferes with the ability of dexamethasone and dibutyryl cyclic AMP to increase production of several specific species of messenger RNA in hepatoma cells. This effect correlates well with its ability to reduce rapid acetylation of histones in HTC cells; we discuss potential roles of rapid histone acetylation in modulating hormonal stimulation of transcription.

Acetylation↗
PubMed1989

Hepatic microsomal enzyme induction and adrenal crisis due to o,p'DDD therapy for metastatic adrenocortical carcinoma.

Two cases are described in which metastatic adrenocortical carcinoma associated with Cushing's syndrome was treated with mitotane (o,p'DDD). The first patient had initially been treated by bilateral adrenalectomy and, whilst responding to mitotane biochemically and by remission of metastases, experienced repeated episodes of adrenal crisis requiring a substantial increase in steroid therapy. The second patient failed to respond to the drug, but evidence of hepatic enzyme induction was noted during its administration. It is suggested that hepatic microsomal enzyme induction can occur in association with treatment with mitotane and that this can lead to an increased destruction of exogenous steroid with clinical consequences.

Addison Disease↗
PubMed1986

Polychlorinated dibenzofurans as 2,3,7,8-TCDD antagonists: in vitro inhibition of monooxygenase enzyme induction.

2,4,6,8- and 1,3,6,8-tetrachlorodibenzofuran (TCDF) competitively displace [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) from the rat cytosolic receptor protein and their EC50 values were 1.5 X 10(-6) and 1.25 X 10(-7) M, respectively. In contrast to their relatively high binding avidities these TCDF isomers were poor inducers of benzo[a]pyrene hydroxylase and ethoxyresorufin O-deethylase in rat hepatoma H-4-II E cells in culture (EC50 greater than 10(-5) M). Coadministration of different concentrations of 2,4,6,8- and 1,3,6,8-TCDF (10(-5), 10(-6) and 10(-7) M) with 2 X 10(-10) M, 2,3,7,8-TCDD (a dose which elicits 80% of the maximal induction response) resulted in significant decreases in the expected (additive) induction of benzo[a]pyrene hydroxylase and ethoxyresorufin O-deethylase by the mixture. Thus the partial agonists, 1,3,6,8- and 2,4,6,8-TCDF, antagonize the receptor-mediated enzyme induction activity of 2,3,7,8-TCDD presumably via competitive displacement of 2,3,7,8-TCDD from the receptor protein. In contrast, coadministration of 2,3,7,8-TCDF and 2,3,7,8-TCDD gave additive enzyme induction responses. The identification of the 2,3,7,8-TCDD antagonists represents a new class of halogenated aryl hydrocarbons.

Animals↗
PubMedDate not supplied

A re-evaluation of intersubject variation in enzyme induction in man.

It has previously been suggested that subjects who are initially slow metabolisers of drugs have a greater potential for induction of their drug metabolising enzymes than subjects with initial high rates of metabolism. This inference is based on observations made of changes in half-life of antipyrine. The purpose of this presentation is to reanalyse data previously presented in the literature with reference to clearance, a more precise estimate of drug metabolising activity, and half-life a parameter derived from both clearance and distribution. In one study in non-obese subjects, approximately 80% of intersubject variation in the change of total antipyrine clearance can be explained by differences in body size, particularly differences in liver volume. Furthermore, the relationship between initial antipyrine half-life and the percentage change in antipyrine half-life following induction can be explained by the association between each parameter and body weight. These observations imply that the potential for enzyme induction, and therefore for drug interactions based on enzyme induction, is present in all subjects and that intersubject variance in steady-state drug concentrations are as wide following induction as before induction.

Antipyrine↗
PubMed1983

Enzyme induction with rifampicin; lipoproteins and drug binding to alpha 1-acid glycoprotein.

Hepatic enzyme induction has been reported to increase lignocaine binding, alpha 1-acid glycoprotein concentration and high density lipoprotein (HDL) cholesterol. In eight volunteers treated with rifampicin for 3 weeks there was no significant alteration in these three variables although their antipyrine clearance was significantly increased. In 10 patients with pulmonary tuberculosis treated with rifampicin (mean 5 months) the degree of serum protein binding of lignocaine, alpha 1-acid glycoprotein and HDL-cholesterol concentration was not different from that of matched control patients. These results suggest that differential induction of these variables may occur.

Adult↗
PubMed1980

Tuberculosis therapy and enzyme induction in man.

The enzymatic inducing effect of an antituberculous treatment (Rifampicin, Isoniazid and Ethambutol) is tested by recording variations in the urinary D-glucaric acid elimination and in the antipyrine half-life test, measured before starting treatment and after two weeks of treatment. This study concerns 21 patients: 14 are slow acetylators and 7 are rapid acetylators of isoniazid. After two weeks of treatment an increase of the urinary glucaric acid elimination is observed but variations in the antipyrine half-life test are not univocal and allow us to separate two categories of patients: 10 have a significant decrease of antipyrine half-life, 11 have not. A link seems to exist between the rapid acetylator phenotype and this enzyme induction which is revealed by the antipyrine test. An interpretation of these two enzyme induction tests, the nature of the rifampicin inducing action and its relation to the acetylator phenotype are discussed.

Acetylation↗
PubMed2001

Hepatic enzyme induction and acute endocrine effects of 2,2',3,3',4,6'-hexachlorobiphenyl and 2,2',3,4',5',6-hexachlorobiphenyl in prepubertal female rats.

Polychlorinated biphenyls (PCBs) with the liable 2,3,6-substitution are important components of certain commercial mixtures and frequently detected in biota, but little is known about their enzyme induction abilities and possible endocrine-disrupting effects. CB 132 (2,2',3,3',4,6'-hexachlorophenyl) and CB 149 (2,2'3,4',5',6-hexachlorophenyl) were investigated in weanling female rats dosed intraperitoneally on days 21 and 22 and killed on day 24 of age. Uterotropic response, serum thyroid hormone, and hepatic enzyme induction were examined in prepubertal female rats treated with these two environmentally relevant 2,3,6-substituted chlorobiphenyl (CB) congeners from 8 mg/kg to 96 mg/kg. The readily metabolized CB 132 did not cause any significant increase in all endpoints measured in the present study. On the other hand, CB 149 was a weak PROD and BROD inducer and a modest depleter of serum thyroxine in prepubertal female rats. The finding of thyroid hormone disruption by CB 149 may lead to biologically significant neurobehavioral and neurochemical changes in developing animals via milk lactation.

Animals↗
PubMed1984

Increased serum gamma-glutamyltransferase activity in renal transplant recipients: liver damage or microsomal enzyme induction?

To investigate the reason for the increased activities of gamma-glutamyltransferase in the serum of renal transplant recipients, the activity of this enzyme was determined together with the alanine aminotransferase and alkaline phosphatase activity in serum (as an index of liver damage) and the urinary excretion of D-glucaric acid (as an index of microsomal enzyme induction) in 63 renal transplant recipients. Forty-one patients had increased activities of gamma-glutamyltransferase. Increased D-glucaric acid excretion was found only in ten patients having elevated alanine aminotransferase and/or alkaline phosphatase in seven cases and gamma-glutamyltransferase in eight cases. Therefore, the increased gamma-glutamyltransferase activities in renal transplant recipients can be primarily considered as a consequence of hepatobiliary dysfunction and not of enzyme induction.

Alanine Transaminase↗
PubMedDate not supplied

Serum modulation of the effects of TCDD on the in vitro antibody response and on enzyme induction in primary hepatocytes.

We have recently reported that the effects of TCDD on the in vitro antibody response can vary considerably depending on the serum conditions used in the culture media. To further investigate this phenomenon, studies were performed to compare the effects of TCDD on both splenocyte antibody responses and P450 enzyme induction (EROD) in primary hepatocytes (HPTC) derived from B6C3F1 and DBA/2 mice when evaluated in the presence of either fetal bovine serum (FBS), newborn calf serum (NBCS) or normal mouse serum (NMS). The latter studies with NMS also included crossovers where splenocytes and HPTC from B6C3F1 mice were cultured in the presence of DBA/2 serum and vice versa. Results with NBCS showed comparable suppression of antibody responses by TCDD in splenocytes from B6C3F1 and DBA/2 mice where we detected IC50 values of 3.0 and 2.8 nM, respectively. In contrast, responses in the presence of NMS showed an Ah-dependency that was characterized by a dose-related suppression of antibody responses by B6C3F1 splenocytes, but a lack of suppression in the responses by DBA/2 splenocytes. Distribution studies with radiolabelled TCDD indicated that the observed profile of activity could not be attributed to a differential uptake of the chemical into splenocytes from B6C3F1 or DBA/2 under the various serum conditions. Serum was also found to modulate the TCDD-induced EROD activity in primary HPTC and the profile of activity was identical to the effects of TCDD on in vitro antibody responses. We observed an enhanced induction of EROD in the presence of NBCS (immunosuppressive conditions) and a lower induction in the presence of FBS (non-immunosuppressive conditions), each giving the same relative magnitude of induction regardless of the mouse strain used as the source of HPTC. In contrast, induction in the presence of NMS showed an Ah-dependency and resulted in a dose-related enhancement in EROD activity in B6C3F1 HPTC but decreased activity in the DBA/2 HPTC. Cross-over studies further showed that the pattern of effects on both splenocytes and HPTC was not altered by changing the strain of mouse used as the source of serum, where each gave equivalent results. These findings demonstrate that the Ah-dependency for the effects of TCDD on both the in vitro antibody response and P450 enzyme induction are modulated by the serum environment in which the cells are exposed. The studies with NMS indicate that it is the genotype of the lymphocyte (i.e., or the HPTC), and not the strain-specific hormone environment, which confers sensitivity to TCDD.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Toxicity and microsomal enzyme induction effects of several polybrominated biphenyls of Firemaster.

Some toxicological and pharmacological effects of 2,4,5,2',5'-penta- (congener 1), 2,3,4,2',4',5'-hexa- (congener 5), 2,4,5,3',4',5'-hexa- (congener 6), 2,3,4,5,3',4',-hexa- (congener 7), and 2,3,4,5,2',3',4'-heptabromobiphenyl (congener 9) were evaluated in male rats given a single 90 mg/kg ip injection and killed seven days later. Only congener 7 depressed body weight gain, spleen and thymus weights, and caused severe histopathological changes in the thymus. Congener 7 caused the largest increase in liver weight and the most changes in liver pathology while congener 1 failed to enlarge this organ and caused the mildest ultrastructural changes. Liver microsomes were isolated and evaluated for enzyme induction from all treated rats except those administered congener 6, which was previously identified as a mixed-type enzyme inducer (Dannan et al., 1978b). All congeners increased the liver microsomal cytochrome P-450 content, but only congener 7 shifted the carbon monoxide difference spectrum absorption maximum to 448.0 nm. The microsomal ethyl isocyanide difference spectrum 455/430 nm ratio was increased the most by congener 7 (3 fold). All congeners increased cytochrome P-450 reductase and microsomal epoxide hydrase activities by nearly 1.5-3 fold. Congener 7 failed to induce aminopyrine-N-demethylase activity but the remaining congeners increased it by 2 fold. Congener 7 was the most effective inducer of benzo[a]pyrene hydroxylase and p-nitrophenol UDP-glucuronyl transferase. These results add to the suggestion that the presence of an ortho halogen on a polyhalogenated biphenyl does not completely abolish toxicity or 3-methylcholanthrene-type microsomal enzyme induction.

Animals↗
PubMed2001

The relationship among microsomal enzyme induction, liver weight and histological change in beagle dog toxicology studies.

The present study represents a retrospective analysis of hepatic microsomal enzyme induction data collected over a period of years for the beagle dog. Comparisons were completed for up to six enzyme activities and P450 content versus histopathological examination of the liver for hepatic changes and serum chemistry data analysis for markers indicative of hepatic injury. In addition, qualitative comparisons were made for these compounds to data reported in the rat by the same authors. In this analysis of canine study data for nine different compounds comprising five different pharmacological classes, significant elevations in several microsomal enzyme activities were observed under study conditions that did not result in liver weight increases, histological changes or serum chemistry changes that would be indicative of hepatocellular or hepatobiliary damage. Despite some species differences in cytochrome P450 homologues, for this compound set, there was clearly a general association between the response in dog liver and that of the rat liver. Compounds that elicited significant increases in more than one canine P450 endpoints were also likely to produce an inductive response in rat liver; however, the magnitude of the response and the P450 endpoint involved were not always identical. We conclude that hepatic drug-metabolizing enzyme induction in the beagle dog liver is typically a benign adaptive response, which parallels that reported previously in the rat.

Animals↗
PubMed1991

Hepatic microsomal enzyme induction and thyroid function in rats treated with high doses of phenobarbital or chlorpromazine.

Rats were treated daily with high doses of phenobarbital or chlorpromazine for 6 weeks. The animals were sacrificed after 1, 2, 4 and 6 weeks of treatment. At each occasion, plasma levels of ASAT, ALAT, LDH, AP, total T4 and T3, free T4 and T3, and TSH were determined. The thyroids and liver weights were recorded, and the microscopical examination was performed on the liver, thyroids and pituitary gland. The results showed hepatic morphological changes indicative of enzyme induction on weeks 1, 2 and 4. During the first 4 weeks, plasma T4 and T3 were decreased in many individuals and increased in few others, and after 6 weeks of treatment the values for T4 and T3 returned to near normal. An increase in ASAT and ALAT was found at the same occasions. Follicular cell hypertrophy in the thyroids was observed during the first 4 weeks of treatment, in both treated groups, and after 6 weeks the thyroid glands returned to normal, except for a few individuals from the phenobarbital group. The present study has shown that the effect of phenobarbital and chlorpromazine on the thyroid gland function is predominantly due to their effect on the peripheral hormone disposition, as a result of the hepatic microsomal enzyme induction.

Animals↗
PubMed1990

Bioimpedance assessment of antipyrine pharmacokinetics before and after enzyme induction.

Bioimpedance (BI) technology, a noninvasive method of measuring body composition, has been previously used to develop a predictive model for metabolic clearance under basal conditions. The present investigation was conducted to assess the ability of BI-derived models to predict drug disposition in a perturbed system. An antipyrine pharmacokinetic and impedance analysis of 15 healthy male subjects was performed before and on the 14th day of phenobarbital administration (i.e., after enzyme induction). The all subsets multiple regression technique was used to develop preinduction models for clearance (CI), (p = 0.021, R2 = 0.654) and volume of distribution at steady-state (Vdss) (p = 0.001, R2 = 0.867), using demographic and mean BI parameters. The preinduction Cl model significantly underestimated postinduction measurements and was not predictive of changes in Cl. The preinduction Vdss model was predictive of postinduction Vdss. It appears that the BI-derived model is unable to predict perturbations in metabolic clearance caused by enzyme induction.

Adult↗