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Mechanism of the enrichment of phosphatidylcholine in liver accompanying enzyme induction by phenobarbital.
The mechanism of the increase of phosphatidylcholine in liver, accompanying enzyme induction by phenobarbital, has been studied in rats. Using radioactively labeled precursors, the two main pathways of phosphatidylcholine biosynthesis--the CDP-choline pathway and the methylation of phosphatidylethanolamine--were analyzed after pretreatment with 4 doses of phenobarbital (80 mg/kg) on 3 consecutive days. After i.v. injection of choline [Me-3H], choline [Me-14C] or NaH2[32P]O4 the specific radioactivity (sp. act.) of phosphatidylcholine (dpm/nmol) was decreased by 60%, and after methionine [Me-3H] or ethanolamine [1.2-14C] by 40% compared to control rats. These changes are partly due to the increased concentration of phosphatidylcholine and phosphatidylethanolamine, causing the incorporated precursors to dilute, and partly to a secondary effect which leads to a reduction of the sp. act. of free choline in pretreated animals. The concentration of glycerylphosphorylcholine, one of the metabolites of phosphatidylcholine catabolism, was also diminished by almost 50%. From these results it may be concluded that the increase of phosphatidylcholine is due to a retardation of its breakdown rather than to an increase of its synthesis.
Hepa-1 enzyme induction assay as an in vitro indicator of the CYP1A1-inducing potencies of laboratory rodent diets in vivo.
The Hepa-1 enzyme induction assay (assay of the induction of CYP1A1 catalytic activities in the Hepa-1 mouse hepatoma cell line by various compounds or mixtures) was evaluated as an in vitro indicator of the CYP1A1-inducing potencies of laboratory rodent diets in vivo. C57BL/6J mice were fed for three weeks four selected commercially available diets (one semisynthetic and three standard natural ingredient diets) exhibiting different enzyme-inducing effects in the Hepa-1 assay. beta-Naphthoflavone mixed in a semisynthetic diet (33 and 330 mg/kg of diet) was used as a model inducer. CYP1A1-dependent enzyme activities (aryl hydrocarbon hydroxylase and 7-ethoxyresorufin O-deethylase) were measured in the small intestinal mucosa and liver. There was good agreement between the induction of CYP1A1 in vitro and in vivo: the rank order of the enzyme activities elicited by the diets was the same in the mice as in the Hepa-1 cells. The standard diets were less effective inducers than beta-naphthoflavone in the Hepa-1 cells and in the mice, especially in the small intestinal mucosa. The Hepa-1 enzyme induction assay thus seems to be a mechanistically sound, reliable and sensitive in vitro indicator of the CYP1A1-inducing potencies of laboratory rodent diets in vivo.
Hepatic enzyme induction and vitamin K1 elimination in man.
We have studied the effect of hepatic enzyme induction on vitamin K1 elimination in patients on long-term anticonvulsant therapy and in volunteers given rifampicin. Neither the anticonvulsants (phenytoin and phenobarbitone) nor rifampicin had any significant effect on vitamin K1 elimination half-life or AUC. The neonatal haemorrhage which occurs in babies born to mothers on long-term enzyme inducing drugs is unlikely to be related to an increased rate of vitamin K elimination in the mother.
Role of rat multidrug resistance protein 2 in plasma and biliary disposition of dibromosulfophthalein after microsomal enzyme induction.
We have previously demonstrated that microsomal enzyme inducers phenobarbital (PB) and pregnenolone-16alpha-carbonitrile (PCN), but not 3-methylcholanthrene (3-MC) and benzo(a)pyrene (BaP), increase expression and function of rat Multidrug Resistance Protein 2 (Mrp2), a canalicular organic anion transporter. Thus, the purpose of this study was to determine whether Mrp2 protein induction alters the biliary and plasma dispositions of dibromosulfophthalein (DBSP). After four daily ip injections of PB, PCN, 3-MC, BaP, or vehicle, DBSP (100 mg/kg) was injected iv and was measured in blood and bile over a 40-min period. PB and PCN significantly enhanced plasma disappearance and biliary excretion of DBSP, whereas 3-MC and BaP did not. To determine whether the enhanced plasma disappearance and biliary excretion was entirely due an increase in Mrp2, PCN was also administered ip daily for 4 days to Mrp2-null Eisai hyperbilirubinemic (EHBR) rats and then injected iv with DBSP. PCN significantly increased plasma DBSP disappearance in EHBR rats during early time intervals (2-20 min), but not at later time intervals (25-40 min). PCN did not increase DBSP biliary excretion in EHBR rats, but actually decreased it at later time intervals. In summary, the increase in Mrp2 protein after microsomal enzyme induction is responsible for increased biliary DBSP excretion. Furthermore, the increase in Mrp2 protein after microsomal enzyme induction is not responsible for the enhanced plasma DBSP disappearance at early time points, yet may influence plasma DBSP disappearance at later time points. This study also demonstrates the importance of compensatory hepatic transporters in eliminating DBSP by alternative pathways other than Mrp2.
Hepatic microsomal enzyme induction by trifluoromethyl compounds and some halogenated and nonhalogenated analogs.
Trifluoromethyl derivatives of toluene, phenothiazine, benzimidazole and DDT were administered ip to male rats for 5 days and induction of hepatic microsomal enzymes catalyzing the metabolism of EPN, p-nitroanisole and aminopyrine measured. The addition of a trifluoromethyl substituent to toluene, phenothiazine and benzimidazole increased the inducing capacity of the parent molecule on p-nitroanisole metabolism. Dihalogenation of benzene with trifluoromethyl groups, regardless of position, resulted in induction of p-nitroanisole metabolism whereas halogenation of benzene with trichloromethyl groups did not. For these compounds, the size and electron-inducing capacity of the halogenated substituent may be relative to microsomal enzyme induction.
Quantitative assessment of enzyme induction by peroxisome proliferators and application to determination of effects on triglyceride biosynthesis in primary cultures of rat hepatocytes.
Potencies for the induction of peroxisomal fatty acyl-CoA oxidase (FACO) and microsomal laurate hydroxylase (LH) were determined for clofibric acid (CPIB), ciprofibrate (Cipro) and gemfibrozil (Gem) in primary cultures of rat hepatocytes based on complete concentration-response analysis and determination of theoretical maximum inductive responses for Cipro. CPIB and Cipro each induced FACO and LH in a concentration-dependent manner. Scatchard analysis of the data allowed calculation of EC50 values (mM) of 0.82 and 0.028 (for FACO) and 0.22 and 0.0081 (for LH) for CPIB and Cipro respectively. The EC50 ratios (CPIB/Cipro) were identical (29-fold) for induction of FACO and LH, supporting the concept that these enzymes are induced by CPIB and Cipro through a common mechanism. By comparison, Gem was relatively ineffective as an inducer of FACO and LH. Furthermore, Gem did not antagonize Cipro-mediated enzyme inductions, suggesting that Gem is a peroxisome proliferator of low potency rather than a partial agonist. Based on the potency and time-course profiles observed for induction of FACO and LH, the effects of CPIB, Cipro and Gem on triglyceride (TG) biosynthesis were determined in the cultured rat hepatocytes. Conditions of maximal FACO and LH induction by the drugs did not result in inhibition of TG biosynthesis in the cells. These results support the in vivo evidence which indicates that FACO and LH induction are not causally linked to the hypotriglyceridemic actions of peroxisome proliferating drugs.
Increased clearance of antipyrine and d-propranolol after phenobarbital treatment in the monkey. Relative contributions of enzyme induction and increased hepatic blood flow.
The effects of phenobarbital treatment for 12 days on the regional distribution of blood flow and on the disposition of two model drugs, antipyrine and d-propranolol, have been determined in six unanesthetized rhesus monkeys. Phenobarbital significantly increased total hepatic blood flow from 179+/-15 to 239+/-27 ml/min. Liver weight was increased to a similar degree (34%) in phenobarbital-treated animals as compared to control monkeys. The clearance of both antipyrine and d-propranolol was increased and the half-life decreased significantly by phenobarbital. Analysis of the data by a perfusion-limited pharmacokinetic model showed that the changes in antipyrine clearance were due almost entirely to enzyme induction. On the other hand, with d-propranolol, the increase in liver blood flow contributed as much to the enhanced clearance as did the stimulation of drug metabolism. The mechanism by which phenobarbital produces the frequently observed increase in drug clearance, therefore, depends upon the initial clearance value of the drug. For low clearance drugs like antipyrine, clearance changes occur largely as a result of enzyme induction. With higher clearance drugs, the effects of increased hepatic blood flow become progressively more important the greater the initial clearance value.
Enzyme induction in neonates after fetal exposure to antiepileptic drugs.
The 13C-AP breath test is shown to be a convenient, noninvasive method to monitor velocity and capacity of P450-dependent AP N-demethylation in infancy and childhood. According to 13C-AP breath tests, neonates have a very low capacity to eliminate 13CO2, which is only 15 to 21% of the activity in adults. During the first year of life AP N-demethylation increases to reach its maximum at about 2 years; afterwards a slight decrease occurs. In 25 neonates exposed prenatally to different antiepileptic drugs 13C-AP breath test was efficiently used to prove that cytochrome AP N-demethylation was considerably stimulated. After primidone/phenobarbitone, especially in combination with phenytoin, 13C elimination reaches and even surpasses the range for older children. Valproate exposure during fetal life is not consistently followed by a significant increase in AP N-demethylation. The enzyme induction demonstrated by 13C-AP breath test was often accompanied by accelerated metabolic clearance and shortened half-life times of transplacentally acquired antiepileptic drugs. There was good agreement between 13C-AP breath tests and pharmacokinetic data for primidone/phenobarbitone but not for phenytoin. In contrast, in the case of phenytoin exposure during pregnancy the pharmacokinetic parameters and the 13C breath test data will transport very different informations about enzyme induction in these neonates.
X-ray sensitivity and target volume of enzyme induction.
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The role of enzyme induction on metabolite formation of bis(2-methoxyethyl) ether in the rat.
The effect of enzyme induction on the metabolism of the reproductive toxicant bis (2-methoxyethyl) ether (diglyme) was studied in male Sprague-Dawley rats. Rats were given either daily doses of diglyme at 5.1 mmol/kg body wt. by gavage or 0.1% (w/v) phenobarbital (PB) in the drinking water for 22 consecutive days. In one study, a significant reduction in the hexobarbital sleeping time was determined for rats pretreated with diglyme or PB in comparison with that determined for naive rats. In a second study, naive and pretreated rats given single oral doses of 14C-diglyme at 5.1 mmol/kg body wt. showed similar urinary 14C excretion patterns. Urinary metabolites were separated and quantified by hplc to evaluate the influence of pretreatment with either diglyme or PB on the 14C-diglyme urinary metabolite profile. The amount of (2-methoxyethoxy) acetic acid, the principal metabolite, was similar for rats given no pretreatment and for rats pretreated with either diglyme or PB. However, both pretreatments resulted in significant increases in the formation of methoxyacetic acid, a recognized reproductive toxicant.
Effect of cannabis on enzyme induction by phenobarbital.
Cannabis extracts in olive oil administered s.c. to male adult rats decreases oxidizing microsomal enzymes measured as TPNH disappearance and AHH activity in liver postmitochondrial fraction (93.06% and 25.54% maximum inhibition respectively in chronic treatments). Simultaneous administration of single doses of cannabis extracts (330 mg/kg s.c.) and phenobarbital (100 mg/kg i.p.) causes impairment of total microsomal oxidases (86.83% inhibition) and decreases AHH (31.86% inhibition), thus blocking the enzyme induction by phenobarbital.
Phenobarbital in the genetically obese Zucker rat. II. In vivo and in vitro assessments of microsomal enzyme induction.
In vivo and in vitro alterations in drug metabolism and the extent of enzyme induction of the hepatic microsomal cytochrome P-450 system were evaluated in obese and lean Zucker and lean Sprague-Dawley rats. Phenobarbital enzyme-inducing regimens were administered p.o. to achieve similar steady-state phenobarbital plasma concentrations. Control rats received p.o. placebo solution. No significant intra- or inter-strain differences in antipyrine clearance (milliliters per hour) or apparent volume of distribution (liters) were observed between the placebo-treated lean Sprague-Dawley, lean Zucker and obese Zucker rats. Intra- and inter-strain differences in hepatic microsomal protein and cytochrome P-450 content were observed. Compared to placebo, antipyrine clearance (milliliters per hour) after chronic phenobarbital pretreatment was increased in the Sprague-Dawley (198%) and lean Zucker rats (131%), but not significantly altered in the obese Zucker rats. Similarly, increases in hepatic weight, whole liver microsomal protein and cytochrome P-450 content were also observed in the Sprague-Dawley (34, 124 and 352%, respectively) and the lean Zucker rats (24, 96 and 249%, respectively). However, no significant alterations in these parameters were observed in the obese Zucker rats after phenobarbital treatment. Results from these in vivo and in vitro studies implicate alterations in drug metabolism and genetic differences in cytochrome P-450 content in Zucker rats relative to the Sprague-Dawley strain. Obese Zucker rats failed to exhibit a significant induction response after phenobarbital pretreatment.
Time course of enzyme induction in humans: effect of pentobarbital on nortriptyline metabolism.
To study the effect of induction we gave six male volunteers 10 mg nortriptyline three times a day for 4 weeks and 0.2 gm pentobarbital on days 8 to 21. Plasma and urinary levels of nortriptyline and metabolites were measured. The rate and extent of induction of the enzyme(s) were estimated by a model with use of nortriptyline concentrations. There was a marked decrease of nortriptyline levels after 2 days of pentobarbital treatment. Total clearance of nortriptyline increased more than twofold (range, 1.6-fold to 4.1-fold). Apparent metabolic clearance by 10-hydroxylation increased markedly. The decrease in nortriptyline levels was more rapid than the increase after pentobarbital cessation, fitting with the theory of the model. The induction of nortriptyline metabolism is probably mainly the result of an increase in a non-CYP 2D6 P450 isozyme, possibly CYP 3A4 or a CYP 2C form. More knowledge of induction characteristics of drugs should lead to better predictions of decreased effects and appearance of adverse effects. The kinetic model used for analysis of our data could then be useful.
[Enzyme induction and anticonvulsants].
Serum gamma-GT-activity was significantly (0.01 greater than P greater than 0.001) elevated in 18 of 30 epileptics receiving carbamazepine (CBZ), i.e. in 60%. The incidence of abnormal gamma-GT-levels in the control group (25 neurotic patients taking minor tranquilizers) was lower (12%). The possible relationships between the enzyme induction or chronic hepatic toxicity and the elevation of serum gamma-GT-activity in epileptics taking CBZ are discussed.
Effect of a new rifamycin derivative, rifalazil, on liver microsomal enzyme induction in rat and dog.
1. The effect of a new rifamycin derivative, rifalazil (KRM-1648), on liver microsomal enzyme induction was studied in rat and dog with repeated oral administration of the compound. Relative liver weight, cytochrome b5 and P450 contents, enzyme activities of NADPH-cytochrome c reductase, aniline hydroxylase, p-nitroanisole O-demethylase, aminopyrine N-demethylase, and erythromycin N-demethylase were measured. 2. In rat, rifalazil treatment at 300 mg/kg/day for 10 days increased cytochrome b5 content but it did not affect liver weight, P450 content or enzyme activities. In contrast, rifampicin and rifabutin increased relative liver weights, cytochrome contents and enzyme activities under similar conditions. 3. In dog, rifalazil did not affect any parameters at 30 or 300 mg/kg/day for 13 weeks. 4. These findings indicate that rifalazil is not an enzyme inducer in rat and dog. This property differs from other rifamycin derivatives such as rifampicin and rifabutin.
Enzyme induction by enflurane in man.
Concentrations of 6-beta-hydroxycortisol (6-OHF), a polar metabolite of cortisol formed in the endoplasmic reticulum (microsomes) of the liver, and 17-hydroxycorticosteroids (17-OHCS) were measured in the urines of six healthy adult male volunteers exposed to a mean of 9.6 MAC-hours of enflurane anesthesia as an index of possible enzyme induction. The ratio of 6-OHF to 17-OHCS in 24-hour urine specimens collected five days before anesthesia was compared with the ratio of these metabolites in 24-hour urine specimens collected 16 to 18 hours after anesthesia. The ratio of 6-OHF to 17-OHCS increased markedly in five and decreased slightly in one volunteer following anesthesia. The results indicate that enflurane may cause induction of hepatic microsomal enzymes.
Possible mechanisms by which information is conveyed to the cell in enzyme induction.
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