Hepatic Microsomal Drug-metabolizing Enzyme Activities Research Articles

Exposure of hemodialysis patients to di-2-ethylhexyl phthalate

The migration of di-2-ethylhexyl phthalate (DEHP) from dialyzers was studied in 21 patients with chronic renal failure undergoing maintenance hemodialysis. The circulating concentrations of DEHP were measured by high performance liquid chromatography in blood of patients obtained from the inlet and the outlet of the dialyzer during a 4-h dialysis session. During treatment of renal failure using plasticized tubing, the plasma level of DEHP increased. On average, an estimated 75.2 mg of DEHP was extracted from the dialyzer during a single dialysis session, with a range of 44.3–197.1 mg. On the other hand, the total amount of DEHP retained by the patient during the dialysis session was evaluated by the difference between the AUC out and the AUC in and ranged from 3.6 to 59.6 mg. The rate of extraction of DEHP from the dialyzer was correlated ( r=0.705, P<0.05) with serum lipid content (cholesterol and triglyceride). So, we confirmed that patients on hemodialysis are always regularly exposed to considerable amounts of DEHP. However, several metabolic effects have been reported in various animal species following treatment with DEHP, such as changes in lipid metabolism and in hepatic microsomal drug-metabolizing enzyme activities. DEHP is now a well-known hepatic peroxisomal proliferator in rodents and an inducer of many peroxisomal and non-peroxisomal enzymes. So, lipid metabolism modifications and hepatic changes observed in hemodialysis patients could be explained from chronic exposition to DEHP. In the coming years, it seems necessary to reconsider the use of DEHP as a plasticizer in medical devices. Highly unacceptable amounts of DEHP leached during the dialysis session could be easily avoided by careful selection of hemodialysis tubing.

肝障害ラットの血清ＧＰＴ値および肝薬物代謝酵素に及ぼすクロルプロマジンの影響

Effects of chlorpromazine (CPZ) on serum GPT (SGPT) and hepatic microsomal drug-metabolizing enzyme activities in the rat with liver injured by CCl4 were studied.Rats were intraperitoneally injected with CCl4 at a dose of 0.2ml/kg every 3 days, and with CPZ at a dose of 5 mg/kg once a day for 48 days. SGPT activity was gradually elevated from the beginning of CCl4-administration and reached to the maximum after 30 days.The elevation of SGPT value induced by CCl4-administration was inhibited by the administration of CPZ.In addition, decreases of cytochrome P-450 and cytochrome b5 by CCl4-administration were observed.However, CPZ restored the decrease of cytochrome P-450.These results indicate that CPZ protects liver cell damage induced by CCl4, resulting in that the effect of CPZ on cytochrome P-450 may be important for protecting from drug-induced hepatic injury.

Effect of Melothria maderaspatana on carbon tetrachloride-induced changes in rat hepatic microsomal drug-metabolizing enzyme activity

Treatment with an aqueous extract of the aerial parts of Melothria maderaspatana, before or after CCl 4 administration in rats markedly decreased CCl 4-mediated reductions in aniline hydroxylase and p-aminopyrine N-demethylase activities. Phenobarbital-induced sleeping time in rats and kinetic enzyme studies showed that the effect of the plant was neither due to an induction of the drug metabolizing enzymes nor due to an alteration in the K m values of the enzymes.

Effect of Dietary β-Carotene on Hepatic Drug-Metabolizing Enzymes in Mice

The effects of dietary supplements of β-carotene (20-500mg per kg diet) on hepatic microsomal drug-metabolizing enzyme activities were studied in mice. Supplementation for 14 days resulted in marked reductions in the concentrations of cytochrome P-450 and biphenyl 4-hydroxylase. The antipyrine N-demethylase and p-nitroanisol O-demethylase activities, however, were unchanged. Also apparently unchanged were the hepatic concentrations of microsomal protein, lipid peroxides, and superoxide dismutase. Supplemental β-carotene was weakly protective against the acute toxic effects of an injection of 1, 2-dimethylhydrazine (DMH), as indicated by a lowered mortality. This anti-carcinogenic action of β-carotene, including a protection against DMH-induced colon carcinogenesis, suggests an alteration by this carotenoid in the metabolism of carcinogens by the liver.

Comparative toxicity in rats of polychlorinated biphenyls (PCBs), polychlorinated quaterphenyls (PCQs) and polychlorinated dibenzofurans (PCDFs) present in rice oil causing "yusho"

To understand the nature of the chemical substances responsible for the disease"Yusho, "a mixture of polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCQs) and polychlorinated dibenzofurans (PCDFs) having a composition similar to that found in the rice oil causing"Yusho"was prepared in our laboratory. Male Sprague-Dawley rats were daily given orally for 22 d a regimen consisting of PCBs, 1 mg/rat/d ; PCQs, 1 mg/rat/d ; PCDFs, 10 μg/rat/d ; or a mixture of PCBs, PCQs and PCDFs (Mixture, (1 mg+1mg+10 μg)/rat/d). Rats treated with PCBs, PCDFs and Mixture showed hepatic enlargement, reduction of serum corticoid level, increase of serum cholesterol level and increase in the hepatic microsomal drug-metabolizing enzyme activity, and the effect was larger in the order of Mixture > PCDFs > PCBs. In addition, when PCDFs or Mixture were administered to rats, atrophy of the thymus and suppression of body weight gain were observed. When Mixture was administered to rats, a significant decrease in serum glutamic pyruvic transaminase (GPT) level and a significant increase in serum triglyceride level were observed. In the PCQs-treated rats, increase in the hepatic microsomal drug-metabolizing enzyme activity and decrease in the adrenal corticoid levels were observed, but the degree of change was far less than that in the PCBs- or PCDFs-treated rats. PCDFs or Mixture showed induction of hepatic microsomal drug-metabolizing enzyme activity of the 3-methylcholanthrene (MC) type in the rat. On the other hand, PCBs and PCQs showed intermediary-type induction of the phenobarbital (PB) and MC types. Therefore, the predominant etiology of"Yusho"may involve PCDFs contained in the toxic rice oil.

Alterations of hepatic delta-aminolevulinic acid synthetase, heme oxygenase, microsomal cytochrome content and drug metabolism in rats bearing ascitic tumors AH 13, AH 66 and AH 414 and a 3-methylcholanthrene induced tumor.

Hepatic microsomal drug-metabolizing enzyme activities, cytochrome content, delta-aminolevulinic acid (ALA) synthetase and heme oxygenase activities were studied in rats bearing ascitic tumors AH 13, AH 66 and AH 414 and a primary, 3-methylcholanthrene (3-MC)-induced, tumor. Hepatic microsomal drug-metabolizing enzyme activities and cytochrome content were decreased in rats transplanted intraperitoneally with 1-2 x 10(6) cells of ascitic tumor cell lines AH 13, AH 66 and AH 414. The extent of the decrease of the microsomal cytochrome content and enzyme activities were dependent on the tumor-bearing periods after inoculation. Hepatic microsomal heme oxygenase activity was significantly increased concurrently with the decrease of microsomal drug-metabolizing enzyme activities and cytochrome content. Hepatic ALA synthetase was not changed appreciably in these tumor-bearing rats. Similar alterations of microsomal enzyme content and activities were observed in the livers of rats transplanted subcutaneously with AH 66 tumor cells and in rats bearing a primary tumor initiated by the subcutaneous injection of 3-MC. When the tumor was surgically removed from the rats bearing AH 66 subcutaneously, these hepatic microsomal parameters returned to normal levels. Microsomal drug-metabolizing enzyme activities and cytochrome content in these ascitic tumor cells were found to be at very low levels. From these results, if appears that there is an inverse relationship between the increase of microsomal heme oxygenase activity and the decrease of cytochrome P-450 and b5 as well as drug-metabolizing enzymes in the liver of tumor bearing rats.

Altered hepatic microsomal drug-metabolizing enzyme activity resulting from experimental infection of rats with Trypanosoma b. brucei.

Infection of experimental rats with Trypanosoma brucei (T. b. brucei) results in a decrease in the activities of aniline hydroxylase, aminopyrine-N-demethylase and a lowering of the level of reduced glutathione in the liver. The activity of cytochrome c reductase remains above normal 50 h after infection. Infection of animals previously treated with either phenobarbitone or 3-methylcholanthrene results in a reduction in the specific activity of aniline hydroxylase and aminopyrine-N-demethylase. However, the specific activity of aromatic hydrocarbon hydroxylase is not depressed in 3-methylcholanthrene-treated rats.

Inhibition of hepatic microsomal drug-metabolizing enzymes by habu snake ( trimeresurus flavoviridis) venom fractions

An inhibitor of hepatic microsomal drug-metabolizing enzyme activity was isolated from the venom of the Habu snake ( Trimeresurus flavoviridis) by gel filtration through Sephadex G-100 and Amberlite CG-50 column chromatography. The inhibitor, designated R-CG-50-2, gave one band on sodium dodecylsulfate (SDS) polyacrylamide gel electrophoresis and caused high hemorrhagic activity when administered i.c. to rabbits. R-CG-50-2 inhibited the drug-metabolizing enzyme system even after being heated at 70° for 5 min, in spite of a complete loss of hemorrhagic activity. Cytochrome P-450 content and NADPH-cytochrome c reductase activity of rat hepatic microsomes were decreased by administration in vivo either R-CG-50-2 or heated R-CG-50-2. The extent of the decrease was greater with unheated R-CG-50-2 than with heated R-CG-50-2. In both cases, cytochrome P-420, the inactive form of cytochrome P-450, was not detected. Lipid peroxidation in hepatic microsomes was also decreased by administration of unheated R-CG-50-2 but the decrease was not significant. In an in vitro experiment, both heated and unheated R-CG-50-2 decreased the cytochrome P-450 content and the NADPH-cytochrome c reductase activity of microsomes, but, unlike the results in vivo, cytochrome P-450 was converted to cytochrome P-420. Microsomal lipid peroxidation was greatly inhibited by either heated or unheated R-CG-50-2 in vitro. It was concluded that the inhibition of the hepatic microsomal drug-metabolizing enzyme system by either heated or unheated R-CG-50-2 may have been due to the decrease in the cytochrome P-450 content and the NADPH-cytochrome c reductase activity, and that lipid peroxidation may not have had an effect on the inhibition.

Hepatic microsomal drug-metabolizing enzyme activity in non-human primates; the effect of repeated oral administration of DDT to baboons and rhesus monkeys

1. Hepatic mocromosal N-demethylase activity was present in the order, rat > baboon > rhesus monkey. By contrast, O-demethylase activity was in the order, rhesus monkey > baboon > rat. Reductase and hydroxylase activities respectively were similar in each species. Chronic administration of DDT to each species caused increases (up to 2-fold) in these enzyme activities, in liver weight and in cytochrome P450 and protein concentrations. Glucuronyltransferase activity was present in the order, rhesus monkey > baboon > rat, and was lowered by DDT treatment. 2. Cytochrome P450 concentrations and O-demethylase activity in baboons were similar to that found in human, and similar to those found previously in baboons. 3. In the rat, increases in Phase I enzyme activities due to DDT treatment, appear to be compensated by increases in a detoxifying Phase II pathway, but this does not appear to be the case in non-human primates; thus the latter species could be more sensitive to toxic agents.

Rifampin-induced methadone withdrawal.

Rifampin alters the clinical efficacy of oral contraceptive and anticoagulant drugs by mechanisms not completely understood. These effects may be due in part to acceleration of their elimination by enhancement of hepatic microsomal drug-metabolizing enzyme activities.1 , 2 Several patients in the Bellevue Chest Service Methadone Maintenance Program complained of the onset of withdrawal symptoms when rifampin was administered for treatment of tuberculosis. None of the patients who received isoniazid or ethambutol (or both) had symptoms of withdrawal once stabilized on methadone maintenance, but in a majority of the patients receiving rifampin withdrawal symptoms developed. Since the isoniazid-rifampin regimen is the most . . .

Effect of acetaldehyde on hepatic microsomal drug-metabolizing enzyme activities in vitro

Effect of acetaldehyde on hepatic microsomal drug-metabolizing enzyme activities in vitro

Some in vitro assay conditions that affect detection and quantitation of phenobarbital-induced increases in hepatic microsomal drug-metabolizing enzyme activity

Different laboratories use a variety of “standard” incubation conditions to assay in vitro for hepatic microsomal drug-metabolizing enzyme activity. Incubation volumes of 3–5 ml often contain 9000 g supernatant fractions or microsomes from 250 mg to 1.0 g of liver. Microsomal protein concentrations in such incubation mixtures will often exceed 2 mg/ml. Many workers do not specify rate of shaking or gas flow rate used in such incubations, and open air rather than flowing oxygen is often the gas phase. Under certain of these “standard” conditions we have been unable to demonstrate increased drug metabolism by hepatic fractions from phenobarbital-treated as compared with control rats. Incubation conditions contributing to this difficulty in demonstrating enzyme induction by phenobarbital were: (1) too much protein; (2) too slow shaking rate; (3) too little agitation of incubation mixtures; and (4) use of open air rather than flowing oxygen as gas phase. Incubation conditions which provided good evidence of the effects of phenobarbital as an inducer of the hepatic microsomal enzymes studied included: (1) microsomal protein concentrations in the incubation mixture of less than 2 mg/ml; (2) shaking rate of 100 oscillations per minute; (3) addition of a glass marble to the incubation mixture; and (4) gassing with oxygen rather than leaving open to the air.

Hepatic microsomal drug-metabolizing enzyme activity in the opossum

Hepatic microsomal drug-metabolizing enzyme activity in the opossum

The effect of chronic phenobarbital administration on some hepatic drug-metabolizing enzyme activities in the rat

Prolonged administration of phenobarbital produces an increase in hepatic microsomal drug-metabolizing enzyme activity in some animals. Burns and Conney 1 gave phenobarbital to dogs for 2 months and found enhanced metabolism of phenylbutazone for as long as 6 weeks after cessation of therapy. In a similar study, Remmer et al. 2,3 noted that canine microsomal enzyme activity, with hexobarbital and aminopyrine as substrates, remained elevated for 2 to 4 months after stopping a 2–3-month course of phenobarbital treatment. A single overdose of hypnotics in man can enhance 4-aminoantipyrine production from Novalgin for as long as 15 days. 2 The activity of microsomal drug-metabolizing enzymes in rat liver during and after chronic phenobarbital administration has not been studied. Using rats, Orrenius and Ernster 4 have shown that formation of formaldehyde from aminopyrine falls to control levels within 6 days after short-term administration of phenobarbital (every day for 5 days). In view of this, four microsomal drug-metabolizing pathways were measured in livers from rats given phenobarbital for varying periods of time up to 2 months. A plateau in rate of hexobarbital metabolism was reached during the treatment with phenobarbital, and a rapid decline in enzyme activity was observed after stopping this treatment.