Effect of hypolipidemic compounds on lauric acid hydroxylation and phase II enzymes

Thomas, Helmut; Schladt, Ludwig; Knehr, Michael; Post, Karin; Oesch, Franz; Boiteux-Antoine, Anne-Francoise; Fournel‐Gigleux, Sylvie; Magdalou, Jacques; Siest, Gérard

doi:10.1016/0006-2952(89)90495-4

Cited by 14 publications

(5 citation statements)

References 40 publications

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“…The induction of peroxisomal enzymes by xenobiotics varies quantitatively in different mammalian species and is maximal in rodents (Reddy and Lalwani 1983;Elcomb and Mitchell 1986;Rodricks and Turnbull 1987;Oesch et al 1988;Thomas et al 1989). Although all strains of rats and mice hitherto studied respond vigorously, there are a few reports indicating strain differences in the extent of induction of peroxisomal enzymes (Butler et al 1988;De Angem et al 1989;Dwivedi et al 1989;Lundgren andDe Pierre 1989, Makowska et al 1990).…”

Section: Introductionmentioning

confidence: 90%

Differences in the response of Sprague-Dawley and Lewis rats to bezafibrate: The hypolipidemic effect and the induction of peroxisomal enzymes

et al. 1992

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The effects of bezafibrate administered at 10 and 50 mg/kg/day for 7 days to male Sprague-Dawley (SD) and Lewis rats were investigated in order to determine the interrelation between the changes in serum and hepatic lipid contents and activities of selected peroxisomal, microsomal and mitochondrial enzymes in the two rat strains. In both strains, bezafibrate effectively reduced serum and hepatic lipids, increased the liver weight, induced a proliferation of peroxisomes, and selectively elevated the activities of carnitine acetyltransferase and of the enzymes of the peroxisomal beta-oxidation system. Moreover, immunoblotting revealed that the drug specifically enhanced the concentration of only those peroxisomal enzymes involved in fatty acid beta-oxidation. The data obtained demonstrate that although the responses initiated by bezafibrate are qualitatively similar in both strains, they differ in their magnitude in a dose-dependent manner, with the Lewis strain exhibiting a more pronounced response than the SD rats. These results show that dose-dependent strain differences as well as the generally known species differences should be taken into account in pharmacological and toxicological evaluations of fibrates in rodents. Furthermore, generalization and extrapolation from rodent studies should be treated with great caution.

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Section: Introductionmentioning

confidence: 90%

Differences in the response of Sprague-Dawley and Lewis rats to bezafibrate: The hypolipidemic effect and the induction of peroxisomal enzymes

et al. 1992

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“…Interestingly, other hypolipidemic drugs that are structurally unrelated to the fibrate series, such as tiadenol or probucol, also specifically stimulated bilirubin glucuronidation [4,45]. This suggests that the presence of a carboxylic group in the molecule was not a prerequisite for induction.…”

Section: Peroxisome Proliferators Induce Selectively the Ugt Forms Inmentioning

confidence: 99%

“…On the other hand, peroxisome proliferators that have different pharmacological properties such as the nonsteroidal anti-inflammatory drug acetylsalicylic acid, and the related compound 3,5-diiodosalicylic acid [22,45], also stimulated the glucuronidation of bilirubin two-fold.…”

Section: Peroxisome Proliferators Induce Selectively the Ugt Forms Inmentioning

confidence: 99%

“…Interestingly, induction of bilirubin UGT by peroxisome proliferators and by the series of carboxylic acids related to clofibric acid is concomitant with that of cytochrome P-450-IVAI (lauric acid 12-hydroxylation) and cytosolic epoxide hydrolase [45]. This suggests that these processes could be under coordinate regulation depending on the physical properties of the inducers.…”

Section: What Is the Mechanism Of Induction Of Ugt Buirubin?mentioning

confidence: 99%

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Peroxisome proliferators as inducers and substrates of UDP‐glucuronosyltransferases

Magdalou

Fournel‐Gigleux

Pritchard

et al. 1993

Biology of the Cell

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Peroxisome proliferators, despite their chemically unrelated structures, share the common property of being able to stimulate the glucuronidation of bilirubin in rodents and, probably, also in man. The aryloxycarboxylic acids (clofibric acid, fenofibrate, bezafibrate, ciprofibrate), tiadenol and probucol, all of which have hypolipidemic properties, as well as the fatty acid-like perfluorodecanoic acid all enhanced the expression of the UDP-glucuronosyltransferase (UGT) form involved in the conjugation of the pigment. This induction is manifested by an increase in the mRNA species encoding the protein with a subsequent increase in the neosynthesis of the corresponding protein in the endoplasmic reticulum. The induction process is concomitant with that of cytochrome P-450-IVA1 and cytosolic epoxide hydrolase, which, like bilirubin UGT, are mainly involved in the metabolism of endogenous substrates. With a series of carboxylic acids related to clofibric acid, it was possible to demonstrate that induction was mediated via specific interactions based on the physicochemical properties of the inducers. Until now, the molecular basis of induction of bilirubin UGT is not known. The peroxisome poliferators that possess a carboxyl group are good substrates of UGT, especially in man. The acylglucuronides formed are known for their instability and reactivity which could contribute to the toxicity encountered in some patients treated with the drugs. There is convincing evidence that UGT bilirubin does not catalyze the glucuronidation of these substances even if the two types of substrate form acylglucuronides.

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“…The mechanism of proliferation of peroxisomes, which is accompanied by increased transcription of the genes of P-oxidation enzymes (Reddy et al, 1986) has been the subject of intensive research, and recent evidence indicates that a subtype of cytochrome P-450, referred to as P-450 IV A1 (also P452), plays a major role (Lock et al, 1989). The activity of this enzyme, which functions as an a-hydroxylase of long-chain hydrophobic xenobiotic compounds, is either absent or very low in non-responsive species such as primates (Makowska et al, 1991) and guinea pigs (Thomas et al, 1989).…”

Section: Yamamoto Voliu Fahimimentioning

confidence: 99%

Investigation of peroxisomal lipid beta-oxidation enzymes in guinea pig liver peroxisomes by immunoblotting and immunocytochemistry.

Yamamoto¹,

Völkl²,

Fahimi³

1992

J Histochem Cytochem.

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We investigated the immunoreactivity of the peroxisomal lipid 0-oxidation enzymes acyl-CoA oxidase, trifunctional protein, and thiolase in guinea pig liver and compared it with that of homologous proteins in rat, using immunoblotting of highly purified peroxisomal fractions and monospecific antibodies to rat proteins. In addition, the immunocytochemical localization of 0-oxidation enzymes in guinea pig liver was compared with that of catalase. All antibodies showed crossreactivity between the two species, indicating that these peroxisomal proteins have been well conserved, although all exhibited some differences with respect to molecular size and, in the case of acyl-CoA oxidase, in frequency of the immunoreactive bands. In the latter case,

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Effect of hypolipidemic compounds on lauric acid hydroxylation and phase II enzymes

Cited by 14 publications

References 40 publications

Differences in the response of Sprague-Dawley and Lewis rats to bezafibrate: The hypolipidemic effect and the induction of peroxisomal enzymes

Differences in the response of Sprague-Dawley and Lewis rats to bezafibrate: The hypolipidemic effect and the induction of peroxisomal enzymes

Peroxisome proliferators as inducers and substrates of UDP‐glucuronosyltransferases

Investigation of peroxisomal lipid beta-oxidation enzymes in guinea pig liver peroxisomes by immunoblotting and immunocytochemistry.

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