Differential induction of hepatic drug-metabolizing enzymes by fenvaleric acid in male rats

Morisseau, Christophe; Derbel, Maher; Lane, Terry R.; Stoutamire, Donald W.; Hammock, Bruce D.

doi:10.1093/toxsci/52.2.148

Cited by 19 publications

(11 citation statements)

References 34 publications

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“…Livers from dogs were obtained from Dr. Medhora (Medical College of Wisconsin, USA). Cytosolic fractions were prepared by differential centrifugation as described (Morisseau et al, 1999a) and frozen at -80°C until used. Protein concentration was quantified using the Pierce BCA assay with bovine serum albumin (BSA) as the calibrating standard.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs

Tsai

Hwang

Morisseau

et al. 2010

European Journal of Pharmaceutical Sciences

143

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Epoxyeicosatrienoic acids that have anti-hypertensive and anti-inflammatory properties are mainly metabolized by soluble epoxide hydrolase (sEH, EC 3.3.2.3). Therefore, sEH has emerged as a therapeutic target for treating various cardiovascular diseases and inflammatory pain. N,N’-Disubstituted ureas are potent sEH inhibitors in vitro. However, in vivo usage of early sEH inhibitors has been limited by their low bioavailability and poor physiochemical properties. Therefore, a group of highly potent compounds with more drug-like physiochemical properties were evaluated by monitoring their plasma profiles in dogs treated orally with sEH inhibitors. Urea compounds with an adamantyl or a 4-trifluoromethoxyphenyl group on one side and a piperidyl or a cyclohexyl ether group on the other side of the urea function showed pharmacokinetic profiles with high plasma concentrations and long half lives. In particular, the inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) not only is very potent with good physiochemical properties, but also shows high oral bioavailability for doses ranging from 0.01 to 1 mg/kg. This compound is also very potent against the sEH of several mammals, suggesting that t-AUCB will be an excellent tool to evaluate the biology of sEH in multiple animal models. Such compounds may also be a valuable lead for the development of veterinary therapeutics.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs

Tsai

Hwang

Morisseau

et al. 2010

European Journal of Pharmaceutical Sciences

143

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“…Cytosolic and microsomal fractions were prepared from liver homogenates of sEH WT and null mice as described earlier (43). Cytosolic and microsomal fractions were prepared from liver homogenates of sEH WT and null mice as described earlier (43).…”

Section: Methodsmentioning

confidence: 99%

Alteration in plasma testosterone levels in male mice lacking soluble epoxide hydrolase

Luria¹,

Morisseau²,

Tsai³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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Soluble epoxide hydrolase (Ephx2, sEH) is a bifunctional enzyme with COOH-terminal hydrolase and NH(2)-terminal phosphatase activities. sEH converts epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), and the phosphatase activity is suggested to be involved in cholesterol metabolism. EETs participate in a wide range of biological functions, including regulation of vascular tone, renal tubular transport, cardiac contractility, and inflammation. Inhibition of sEH is a potential approach for enhancing the biological activity of EETs. Therefore, disruption of sEH activity is becoming an attractive therapeutic target for both cardiovascular and inflammatory diseases. To define the physiological role of sEH, we characterized a knockout mouse colony lacking expression of the Ephx2 gene. Lack of sEH enzyme is characterized by elevation of EET to DHET ratios in both the linoleate and arachidonate series in plasma and tissues of both female and male mice. In male mice, this lack of expression was also associated with decreased plasma testosterone levels, sperm count, and testicular size. However, this genotype was still able to sire litters. Plasma cholesterol levels also declined in this genotype. Behavior tests such as anxiety-like behavior and hedonic response were also examined in Ephx2-null and WT mice, as all can be related to hormonal changes. Null mice showed a level of anxiety with a decreased hedonic response. In conclusion, this study provides a broad biochemical, physiological, and behavioral characterization of the Ephx2-null mouse colony and suggests a mechanism by which sEH and its substrates may regulate circulating levels of testosterone through cholesterol biosynthesis and metabolism.

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“…Cytosolic enzyme extracts were prepared in sodium phosphate buffer (100 mM, pH 7.4) as described. 43 The preparations were frozen at −80 °C until used. Protein concentration was quantified using the Pierce BCA assay (Pierce, Rockford, IL) using bovine serum albumin (BSA) as the calibrating standard.…”

Section: Enzyme Preparationmentioning

confidence: 99%

Orally Bioavailable Potent Soluble Epoxide Hydrolase Inhibitors

Hwang

Tsai²,

Liu³

et al. 2007

J. Med. Chem.

215

262

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A series of N,N′-disubstituted ureas having a conformationally restricted cis-or trans-1,4-cyclohexane α to the urea were prepared and tested as soluble epoxide hydrolase (sEH) inhibitors. This series of compounds showed low nanomolar to picomolar activities against recombinant human sEH. Both isomers showed similar potencies, but the trans isomers were more metabolically stable in human hepatic microsomes. Furthermore, these new potent inhibitors show a greater metabolic stability in vivo than previously described sEH inhibitors. We demonstrated that trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid 13g (t-AUCB, IC 50 = 1.3 ± 0.05 nM) had excellent oral bioavailability (98%, n = 2) and blood area under the curve in dogs and was effective in vivo to treat hypotension in lipopolysaccharide challenged murine models.

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Differential induction of hepatic drug-metabolizing enzymes by fenvaleric acid in male rats

Cited by 19 publications

References 34 publications

Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs

Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs

Alteration in plasma testosterone levels in male mice lacking soluble epoxide hydrolase

Orally Bioavailable Potent Soluble Epoxide Hydrolase Inhibitors

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