Cytochrome <i>P</i>-450 induction by clofibrate. Purification and properties of a hepatic cytochrome <i>P</i>-450 relatively specific for the 12- and 11-hydroxylation of dodecanoic acid (lauric acid)

Gibson, Gordon; Orton, Terry C.; Tamburini, Paul P.

doi:10.1042/bj2030161

Cited by 223 publications

(52 citation statements)

References 14 publications

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“…The increased volume density of these organelles is accompanied by induction ofperoxisomal 3-oxidation and microsomal cytochrome P452-mediated fatty acid hydroxylation (4)(5)(6). These properties are shared with many hypolipidemic drugs (e.g., clofibrate, fenofibrate, ciprofibrate) and a variety of other chemicals such as phenoxyacetic acid herbicides (7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

Elcombe¹,

Mitchell²

1986

Environ Health Perspect

163

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The exposure of cultured rat hepatocytes to mono(2-ethylhexyl)phthalate (MEHP) for 72 hr resulted in marked induction of peroxisomal enzyme activity (13-oxidation; cyanide-insensitive palmitoyl CoA oxidase) and concomitant increases in the number of peroxisomes. Similar treatment of cultured guinea pig, marmoset, or human hepatocytes revealed little or no effect of MEHP. In order to eliminate possible confounding influences of biotransformation, the proximate peroxisome proliferator(s) derived from MEHP have been identified. Using cultured hepatocytes these agents were found to be metabolite VI [mono(2-ethyl-5-oxohexyl) phthalate] and metabolite IX [mono(2-ethyl-5-hydroxyhexyl) phthalate]. The addition of these "active" metabolites to cultured guinea pig, marmoset, or human hepatocytes again revealed little effect upon peroxisomes or related enzyme activities (peroxisomal 1-oxidation or microsomal lauric acid hydroxylation). These studies demonstrate a marked species difference in the response of hepatocytes to MEHP-elicited peroxisome proliferation. Preliminary studies have also suggested that peroxisome proliferation due to MEHP may be due to an initial biochemical lesion of fatty acid metabolism.

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Section: Introductionmentioning

confidence: 99%

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

Elcombe¹,

Mitchell²

1986

Environ Health Perspect

163

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“…Specifically, NADPH and carbon monoxide were used to evaluate P450 metabolism, while NAD was used as a dehydrogenase cofactor. Clofibric acid is a known inducer of CYP4A and ␤-oxidation (Gibson et al, 1982). Moreover, ABT was used to inhibit CYP4A.…”

Section: Methodsmentioning

confidence: 99%

In Vitro Metabolism of the Mammalian Soluble Epoxide Hydrolase Inhibitor, 1-Cyclohexyl-3-Dodecyl-Urea

Watanabe¹,

Morisseau²,

Newman³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The metabolism of the soluble epoxide hydrolase (sEH) inhibitor, 1-cyclohexyl-3-dodecyl-urea (CDU), was studied in rat and human hepatic microsomes. The microsomal metabolism of CDU enhanced sEH inhibition potency of the reaction mixture and resulted in the formation of several metabolites. During the course of this study, a sensitive and specific high-performance liquid chromatography with tandem mass spectrometry analytical method was developed to investigate simultaneously the production of these metabolites. In both rat and human hepatic microsomes, CDU was ultimately transformed into the corresponding -carboxylate; however, the rodent tissue appeared to perform this transformation more rapidly. After a 60-min incubation in rat hepatic microsomes, the percentage of residual CDU, the -carboxylate, and the intermediary -hydroxyl were about 20%, 20%, and 50%, respectively. Carbon monooxide inhibited the metabolism of CDU by rat hepatic microsomes, suggesting that the initial step is catalyzed by cytochrome P450. Further metabolism was enhanced by the addition of NAD, suggesting that dehydrogenases are associated with intermediate metabolic steps. Regardless, the ultimate product of microsomal metabolism, 12-(3-cyclohexyl-ureido)-dodecanoic acid, is also an excellent sEH inhibitor with several hundred-fold higher solubility, supporting the hypothesis that CDU has prodrug characteristics. These findings will facilitate the rational design and optimization of sEH inhibitors with better physical properties and improved metabolic stability.Epoxide hydrolases (EH 1 ; EC 3.3.2.3) are enzymes that add water to epoxides (Oesch, 1973). These enzymes are widely distributed throughout the animal and plant kingdoms and not only metabolize epoxides of drugs and xenobiotics, but also catalyze the hydration of endogenous compounds. In mammals, the microsomal EH and soluble EH (sEH), which detoxify mutagenic, carcinogenic, and xenobiotic epoxides (Wixtrom et al., 1985), have broad and complementary substrate selectivities . The sEH rapidly hydrates fatty acid epoxides (Gill and Hammock, 1979) and seems especially involved in the metabolism of epoxides of arachidonic acid (Chacos et al., 1983;Halarnkar et al., 1989;Zeldin et al., 1995) and linoleic acid (Moghaddam et al., 1997;Zheng et al., 2001). Epoxides of arachidonic acid (epoxyeicosatrienoic acids) are endogenous regulators (Capdevila et al., 2000) that influence blood pressure by modulating cardiac output, vascular resistance, renal fluid, and electrolyte balance, whereas the diols of linoleate epoxides have been implicated in inflammatory disorders, such as acute respiratory distress syndrome (Moghaddam et al., 1997), and may be endogenous regulators of vascular permeability and inflammation (Slim et al., 2001). Therefore, the modulation of endogenous lipid epoxides using sEH inhibitors may have therapeutic benefits in both hypertensive and inflammatory conditions. The development of potent and stab...

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“…Although rapid and simple, this method does not separate ll-and 12-hydroxylauric acids effectively; (ii) an advanced HPLC technique to separate 1 l-and IZhydroxylauric acids using a non-isocratic gradient and radiochemical detection [7]. We report here a new method of separating lland 12-hydroxyacids by high resolution capillary gas chromatography coupled with flame ionization detection that provides the accuracy and sensitivity required to measure the formation of these hydroxyacids without using radiolabeled lauric acid as substrate.…”

Section: Introductionmentioning

confidence: 99%

Evidence for the induction of cytochrome P‐452 in rat liver by Aroclor 1254, a commercial mixture of polychlorinated biphenyls

et al. 1989

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We have examined the ability of a commercial mixture of polychlorinated biphenyls (Aroclor 1254) to induce hepatic cytochrome P-4X?-linked enzyme activities in rat and pigeon liver five days after its intraperitoneal injection. The results provide evidence that, at the doses used, Aroclor 1254 induces cytochrome P-452-linked enzyme activities in rats, but not in pigeons. This inductive effect was previously regarded as being specific for hypolipidemic drugs and phthalate ester plasticisers.

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Cytochrome P-450 induction by clofibrate. Purification and properties of a hepatic cytochrome P-450 relatively specific for the 12- and 11-hydroxylation of dodecanoic acid (lauric acid)

Cited by 223 publications

References 14 publications

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms.

In Vitro Metabolism of the Mammalian Soluble Epoxide Hydrolase Inhibitor, 1-Cyclohexyl-3-Dodecyl-Urea

Evidence for the induction of cytochrome P‐452 in rat liver by Aroclor 1254, a commercial mixture of polychlorinated biphenyls

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