Characterization of cytochromes P450 in liver and kidney of rats treated with di‐(2‐ethylhexyl)phthalate

Okita, Janice R.; Castle, Pamela J.; Okita, Richard T.

doi:10.1002/jbt.2570080305

Cited by 44 publications

(27 citation statements)

References 29 publications

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“…In both cases CYP4A1 showed the largest increase in mRNA levels that partially reflects its low constitutive expression. Coordinate induction of the hepatic CYP4A genes has also been demonstrated for the chemical inducers clofibrate, dehydroepiandrosterone, and diethylhexylphthalate (11,29,50,51). Clofibrate showed preferential induction of CYP4A1, inducing CYP4A1 mRNA levels 39-fold in male rat liver microsomes and CYP4A2 and CYP4A3 levels only 8 -10-fold (50).…”

Section: Discussionmentioning

confidence: 90%

Peroxisome Proliferator-activated Receptor α Controls the Hepatic CYP4A Induction Adaptive Response to Starvation and Diabetes

Kroetz¹,

Yook²,

Costet³

et al. 1998

Journal of Biological Chemistry

193

141

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The hepatic CYP4A enzymes are important fatty acid and prostaglandin -hydroxylases that are highly inducible by fibric acid hypolipidemic agents and other peroxisome proliferators. Induction of the CYP4A enzymes by peroxisome proliferators is mediated through the nuclear peroxisome proliferator-activated receptor ␣ (PPAR␣). Fatty acids have recently been identified as endogenous ligands of PPAR␣, and this receptor has been implicated in the regulation of lipid homeostasis. In the present report we characterized the induction of the hepatic CYP4A genes in rats during the altered lipid metabolism associated with starvation and diabetes. The mRNA levels of CYP4A1, CYP4A2, and CYP4A3 were induced 7-17-fold in the livers of fasted animals and 3-8-fold in the livers of diabetic animals. This was accompanied by corresponding changes in CYP4A protein levels and arachidonic and lauric acid -hydroxylase activity. Interestingly, feeding animals after the fasting period caused as much as an 80% suppression of CYP4A mRNA levels, whereas CYP4A protein levels and functional activity returned to control values. A second PPAR␣-responsive gene, acyl-CoA oxidase, was also induced in rat liver by diabetes and fasting. By using PPAR␣-deficient mice, we unambiguously demonstrated that PPAR␣ is strictly required for hepatic CYP4A induction by starvation and diabetes. Similarly, induction of hepatic thiolase and bifunctional enzyme also required expression of PPAR␣. This represents the first evidence for the pathophysiologically induced activation of a nuclear receptor.

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Section: Discussionmentioning

confidence: 90%

Peroxisome Proliferator-activated Receptor α Controls the Hepatic CYP4A Induction Adaptive Response to Starvation and Diabetes

Kroetz¹,

Yook²,

Costet³

et al. 1998

Journal of Biological Chemistry

193

141

View full text Add to dashboard Cite

show abstract

“…Furthermore, the cortical vasculature, particularly preglomerular blood vessels, possesses a high capacity to generate 20-HETE (36,37). These differences are reflected in the greater capacity of cortical as compared with medullary microsomes to transform AA to HETEs (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Renal cytochrome P450 ω-hydroxylase and epoxygenase activity are differentially modified by nitric oxide and sodium chloride

Oyekan¹,

Youseff²,

Fulton³

et al. 1999

J. Clin. Invest.

122

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“…Rat intestinal microsomes and male rat liver microsomes were prepared from adult Sprague-Dawley rats using a procedure adopted from the literature with minor modification (Okita et al, 1993;Chen et al, 2003). The resulting microsomes were suspended in 250 mM sucrose solution, separated into microcentrifuge tubes, and stored at Ϫ80°C until use.…”

Section: Methodsmentioning

confidence: 99%

Disposition of Flavonoids via Enteric Recycling: Enzyme-Transporter Coupling Affects Metabolism of Biochanin A and Formononetin and Excretion of Their Phase II Conjugates

Jia¹,

Chen²,

Lin³

et al. 2004

J Pharmacol Exp Ther

111

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The purpose of this study was to continue our effort to determine how enzyme-transporter coupling affect disposition of flavonoids. The rat intestinal perfusion and Caco-2 cell models were used together with relevant microsomes. In perfusion model, isoflavone (i.e., formononetin and biochanin A) absorption and subsequent excretion of its metabolites were always site-dependent. Maximal amounts of intestinal and biliary conjugates excreted per 30 min were 31 and 51 nmol for formononetin, more than that for pure biochanin A (12 and 20 nmol). When a standardized red clover extract (biochanin A/formononetin ϭ 10:7) was used, the results indicated that more metabolites of biochanin A than formononetin were found in the perfusate (36.9 versus 22.8 nmol) and bile (78 versus 51 nmol). In metabolism studies, rat intestinal and liver microsomes always glucuronidated biochanin A faster (p Ͻ 0.05) than formononetin, whereas intestinal microsomes glucuronidated both isoflavones faster (p Ͻ 0.05) than liver microsomes. However, rapid metabolism in the microsomes did not translate into more efficient excretion in either the rat perfusion model as shown previously or in the Caco-2 model. In the Caco-2 model, both isoflavones were rapidly absorbed, efficiently conjugated, and the conjugates excreted apically and basolaterally. More formononetin conjugates were excreted than biochanin A when used alone, but much more biochanin A conjugates were found when using the isoflavone mixture. In conclusion, efficiency of enzyme-transporter coupling controls the amounts of metabolites excreted by the intestine and liver and determines the relative contribution of enteric and enterohepatic recycling to the in vivo disposition of isoflavones.Red clover (Trifolium pratense L.) extracts are sold as dietary supplements in supermarkets and health food stores in both industrialized and developing countries. Several defined extracts of red clover are sold in the United States to treat women who suffer from menopausal-related symptoms (Rijke et al., 2001;Oleszek and Stochmal, 2002). The extracts are available as tablets (e.g., Promensil), capsules, tea, liquid preparations, and several other forms. Limited clinical studies have demonstrated the effectiveness of Promensil in the management of hot flashes (van de Weijer and Barentsen, 2002), although the efficacy of such products is not always consistent (Baber et al., 1999;St. Germain et al., 2001).Red clover extract contains many of the same isoflavones as soy (Lin et al., 2000). However, a majority of isoflavones in red clover are present in aglycone forms, whereas they are present as glucosides in soy and soy extracts. Furthermore, the principal isoflavones are biochanin A and formononetin in red clover but are genistein and daidzein in soy. Nevertheless, these isoflavones all have similar biological activities, and biochanin A and formononetin can be converted to genistein and daidzein by cytochrome P450 (Tolleson et al., 2002;Hu et al., 2003b). Moreover, daidzein can be metabolized to h...

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Characterization of cytochromes P450 in liver and kidney of rats treated with di‐(2‐ethylhexyl)phthalate

Cited by 44 publications

References 29 publications

Peroxisome Proliferator-activated Receptor α Controls the Hepatic CYP4A Induction Adaptive Response to Starvation and Diabetes

Peroxisome Proliferator-activated Receptor α Controls the Hepatic CYP4A Induction Adaptive Response to Starvation and Diabetes

Renal cytochrome P450 ω-hydroxylase and epoxygenase activity are differentially modified by nitric oxide and sodium chloride

Disposition of Flavonoids via Enteric Recycling: Enzyme-Transporter Coupling Affects Metabolism of Biochanin A and Formononetin and Excretion of Their Phase II Conjugates

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