Induction of cytosolic clofibroyl-CoA hydrolase activity in liver of rats treated with clofibrate
Rolf K. BergeErik StenslandAsle AarslandGhezai TsegaiHarald OsmundsenNiels AarsætherDag Rune Gjellesvik
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Clofibrate
Hydrolase
Specific activity
21 patients with primary hyperlipoproteinemias of type IIb and IV were treated for 8 weeks with placebo, 8 weeks with 0.3 g butylbiguanide and 1.5 g clofibrate/day and then for 8 weeks with 1.5 g clofibrate/day. In 12 patients a second placebo phase of 8 weeks followed. After 8 weeks of combined treatment with butylbiguanide and clofibrate the serum triglycerides decreased from 725 mg to 269 mg/100 ml. During the following period of clofibrate treatment the serum triglycerides increased after 4 and 8 weeks to 326 mg and 306 mg/100 ml respectively. The combined treatment with 0.3 g butylbiguanide and 1.5 g clofibrate/day is more effective in lowering elevated serum triglycerides and cholesterol than 1.5 g clofibrate alone.
Clofibrate
Serum cholesterol
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In a double-blind, randomized study which lasted 48 weeks the effects of clofibrate and halofenate were compared in maturity-onset diabetics with hyperlipidaemia. With the use of both clofibrate and halofenate serum cholesterol values were lowered only slightly. Both agents significantly reduced triglyceride values, but the decreases were modest and transient. Both drugs significantly lowered serum urate values, although the effect of halofenate was distinctly greater. Halofenate, but not clofibrate, had a considerable hypoglycaemic effect on the patients, most of whom were also receiving oral antidiabetic medicines. The drugs produced a number of clinical and biochemical adverse reactions, and in about 20% of all patients the trial had to be discontinued prematurely. The management of hyperlipidaemia in maturity-onset diabetics is briefly discussed, and it is concluded that neither clofibrate nor halofenate is to be recommended.
Clofibrate
Hyperlipidemia
Serum cholesterol
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Clofibrate
Hydrolase
Specific activity
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6-Aminochrysene was converted into mutagen(s), in the Ames test in the presence of Aroclor 1254-induced hepatic S9, microsomal and cytosolic fractions, the first being the least and the last the most efficient activation system. The cytosolic activation of 6-aminochrysene decreased in the presence of increasing amounts of microsomes. The Aroclor 1254-induced rat microsomal and cytosolic systems differed markedly in a number of properties, including their cofactor requirements and responses to prototype inducers of the cytochrome P450-dependent mixed-function oxidase system. The cytosolic activation system could also convert 2-aminochrysene to mutagens but not 2- and 6-methylchrysene. Human hepatic cytosol could convert 6-aminochrysene and 2-aminoanthracene to mutagens in the Ames test. It is concluded that a hepatic cytosolic oxygenase exists, totally different from the microsomal oxygenases, which metabolizes aminopolycyclic aromatic hydrocarbons to mutagens, presumably through N-oxidation. This oxygenase activity appears to be present in human hepatic cytosol.
Microsoma
Ames test
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Metabolism of the hepatocarcinogen, N,N-dimethyl-4-aminoazobenzene (DAB) by rat liver microsomes proceeds via N-demethylation, ring hydroxylation, and azoreduction. DAB azoreduction was induced in microsomes from rats treated with the hypolipidemic drug, clofibrate, whereas oxidative metabolism of the carcinogen was inhibited. In contrast, treatment with nafenopin, another hypolipidemic drug, inhibited microsomal azoreduction of DAB, whereas oxidative pathways were only slightly affected. No direct effect of either drug on azoreductase activity was observed. Both drugs markedly induced microsomal laurate hydroxylation. DAB azoreduction was increased slightly in microsomes from rats treated with beta-naphthoflavone while treatment with phenobarbital led to partial inhibition. Pretreatment with isosafrol or pregnenolone-16 alpha-carbonitrile did not significantly alter DAB reduction. Metyrapone, added in vitro, inhibited microsomal DAB azoreductase activity only in phenobarbital-treated microsomes, whereas alpha-napthoflavone and SKF 525-A inhibited activity in control and all induced microsomes. DAB azoreduction proceeds readily in air and is not sensitive to carbon monoxide. Neither clofibrate nor nafenopin affected NADPH-cytochrome c reductase activity. It is concluded that clofibrate-induced azoreductase activity is probably attributable to a specific isoform of cytochrome P-450 which can be distinguished from those which catalyze oxidative pathways of DAB or laurate hydroxylation.
Clofibrate
Phenobarbital
Microsoma
Hydroxylation
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Antiestrogen
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The in vitro examination of adult male rat prostatic 3α-hydroxysteroid dehydrogenase (3αOHD) activity using 5α-dihydrotestosterone4 as substrate indicates that significant levels of enzyme activity are associated with purified nuclei as well as with the cytosol fractions. Both the purified nuclear and the cytosol fractions exhibited higher levels of 3αOHD activity with NADH than with NADPH. The pH activity curves for the NADH and NADPH catalyzed reactions were different for both the nuclear and cytosol fractions. The results suggest the presence of a number of 3αOHD enzymes in rat prostate.
Dihydrotestosterone
Hydroxysteroid Dehydrogenases
Hydroxysteroid Dehydrogenases
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Clofibrate
Hydrolase
Microsoma
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Abstract— Three enzymes of cholesterol ester metabolism, a cholesterol‐esterifying enzyme which incorporates free fatty acids into cholesterol esters without participation of CoA, and two cholesterol ester hydrolases with differing pH optima, all showed distinct changes in developing rat brains. The specific activity of the esterifying enzyme was approx. 20 percent of the adult level at birth, increased gradually to the adult level by 20 days of age and remained constant thereafter. The pH 4.2 hydrolase at birth also had a specific activity of about 20 per cent of the adult level but it increased rapidly to reach a peak at 13 days, by which time the activity had increased eight‐fold. The activity declined somewhat thereafter to reach the adult level by 23–30 days. In contrast, there already was 60 per cent of the adult specific activity of the pH 6.6 cholesterol ester hydrolase at birth. The activity remained constant until 12 days and then doubled during the next two weeks, reaching a broad peak, then declining slightly to reach the adult activity by 50 days. Therefore, the developmental changes of both of the hydrolases appeared to be related to the process of myelination. The period of active myelination (10–30 days) was characterized by the sharp rise in the activity of pH 6.6 cholesterol ester hydrolase and by the rapid decrease of pH 4.2 cholesterol ester hydrolase.
Hydrolase
Specific activity
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Thiolase
Specific activity
Transferase
Acetyl-CoA
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