The Small Intestine as a Xenobiotic-Metabolizing Organ

Kaminsky, Laurence S.; Zhang, Qingyu

doi:10.1124/dmd.31.12.1520

Cited by 203 publications

(156 citation statements)

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“…As CYP2C is the second most abundant CYP subfamily in the human intestine, its putative regulation by 1,25(OH) 2 D 3 in this tissue could be highly relevant (Drocourt et al 2002, Chen & Goldstein 2009). Phase II enzymes conjugate different charged groups to the compounds previously modified by phase I enzymes, which increases their solubility in water and facilitate their excretion (Kaminsky & Zhang 2003). In CaCo-2 cells, 1,25(OH) 2 D 3 activates the transcription of SULT2A1, a phase II sulphotransferase that acts preferentially on hydroxysteroids and cholesterolderived sterol bile acids, but may also modify several drugs and other xenobiotics (Echchgadda et al 2004).…”

Section: Angiogenesismentioning

confidence: 99%

“…In addition, 1,25(OH) 2 D 3 regulates the expression of vascular endothelial growth factor (VEGFA) and thrombospondin-1 (THBS1), two major opposing factors that control tumour angiogenesis, leading to a balanced change in the angiogenic potential of SW480-ADH cells (Fernández-García et al 2005 (Kaminsky & Zhang 2003). In CRC cells, 1,25(OH) 2 D 3 induces the expression of CYP3A4, the member of the CYP super-family most expressed in the intestine (Thummel et al 2001, Thompson et al 2002, Pfrunder et al 2003.…”

Section: Angiogenesismentioning

confidence: 99%

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Vitamin D and colon cancer

Перейра¹,

Larriba²,

Múñoz³

2012

Endocrine-Related Cancer

110

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The most active vitamin D metabolite, 1α,25-dihydroxyvitamin D3(1,25(OH)2D3), is a pleiotropic hormone with wide regulatory actions. Classically, vitamin D deficiency was known to alter calcium and phosphate metabolism and bone biology. In addition, recent epidemiological and experimental studies support the association of vitamin D deficiency with a large variety of human diseases, and particularly with the high risk of colorectal cancer. By regulating the expression of many genes via several mechanisms, 1,25(OH)2D3induces differentiation, controls the detoxification metabolism and cell phenotype, sensitises cells to apoptosis and inhibits the proliferation of cultured human colon carcinoma cells. Consistently, 1,25(OH)2D3and several of its analogues decrease intestinal tumourigenesis in animal models. Molecular, genetic and clinical data in humans are scarce but they suggest that vitamin D is protective against colon cancer. Clearly, the available evidence warrants new, well-designed, large-scale trials to clarify the role of vitamin D in the prevention and/or therapy of this important neoplasia.

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Section: Angiogenesismentioning

confidence: 99%

Section: Angiogenesismentioning

confidence: 99%

Vitamin D and colon cancer

Перейра¹,

Larriba²,

Múñoz³

2012

Endocrine-Related Cancer

110

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“…The analysis of P450 in human GIT revealed that CYP2C, CYP1A1, CYP3A4, CYP2D6, and CYP2J2 are expressed (Obach et al, 2006). Analysis of P450 mRNA expression in rat intestine demonstrated that CYP3A1, 2B1, 2C6, 2C11, 1A1, and 2D1-4 could be detected in significant amounts (Hiroi et al, 1998;Kaminsky and Zhang, 2003;Lindell et al, 2003). For CYP2C11 and CYP2C12 a gender-dependent protein expression has been published based on liver, with CYP2C11 being exclusively expressed in the male and CYP2C12 in the female rat (Mugford and Kedderis, 1998).…”

mentioning

confidence: 99%

Characterization of Cytochrome P450 Protein Expression along the Entire Length of the Intestine of Male and Female Rats

Mitschke

Reichel²,

Fricker³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Intestinal cytochrome P450 (P450) proteins play an important role in the biotransformation of drugs and may significantly limit their oral absorption and bioavailability. Therefore, we have investigated the amount of P450 proteins via Western blot analysis along the entire intestine of male and female rats. Despite of the use of an inbred rat strain, controlled housing conditions for the animals, and a timed sample preparation, high interindividual differences in the expression of all P450 proteins was observed. CYP3A (135-243 fmol/mg of protein) and CYP2B1 (107-645 fmol/mg of protein) were the most abundant P450 isoforms in the duodenum and jejunum of rat intestine but were present in neither the ileum nor the colon. Compared with CYP2B1 and CYP3A, CYP2D1 (25-71 fmol/mg of protein) and CYP2C6 (3-10 fmol/mg of protein) were only expressed in minor amounts. CYP2C11 could not be identified in the entire rat intestine. In conclusion, this is the first systematic evaluation and quantification of the expression of P450 proteins along the entire length of the intestine in both male and female rats. These data will provide a basis for a better understanding of the extent of intestinal metabolism along the gastrointestinal tract.Absorption through the gut is a key step in the oral delivery of drugs. The main interface between gut lumen and the bloodstream is an epithelial cell layer consisting of polarized enterocytes controlling the passage of exogenous substances into the portal circulation. Enterocytes have a variety of structural features, including tight junctions reducing paracellular permeability, numerous drug transporters, and a set of metabolic enzymes that may all affect the entry of drugs into the body. The extent to which a drug is absorbed also depends on the intrinsic properties of the compound such as solubility, permeability, efflux or uptake transport properties, and susceptibility to metabolic degradation (Martinez and Amidon, 2002;Benet et al., 2004).Although the liver is known as the major site of first-pass extraction, recent studies have indicated that the small intestine also contributes significantly to the first-pass metabolism of many drugs, e.g., cyclosporine (Wu et al., 1995), nifedipine (Iwao et al., 2002), midazolam (Paine et al., 1996, and diltiazem (Iwao et al., 2004). It is known that several uptake and efflux transporter and P450 isoforms are expressed in the human and rat intestine (van de Kerkhof et al., 2007). If a drug is a substrate of efflux transporters, it may enter and exit the enterocytes several times, and, with each cycle, small quantities may be metabolized by cytochrome P450 (P450) enzymes localized in the endoplasmic reticulum. The P450 enzymes belong to a superfamily of heme proteins that show a broad substrate specificity, with substrates ranging in size from ethylene (M r 28) to cyclosporine (M r 1201) (Isin and Guengerich, 2007). Although the liver is regarded as the main organ of drug metabolism, P450 proteins are also expressed in other tissues, e.g., kidn...

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“…CYP1A and 3A isoforms were primarily expressed in rat intestine, whereas CYP2C was not detectable in rat intestine using RT-PCR and immunoblot analysis [24] . Thus, the significant increase in AUC of losartan after oral administration with losartan and ticlopidine (10 mg/kg) may be attributable to the inhibition of CYP2C and 3A subfamilies-mediated losartan metabolism in the liver and/or the intestine rather than the inhibition of P-gp activity by ticlopidine.…”

Section: Discussionmentioning

confidence: 99%

Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats

Yang

Cho

2011

Acta Pharmacol Sin

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npg IntroductionLosartan (DuP 753,, an angiotensin II receptor antagonist, has a low side-effect profile and is approved for the treatment of hypertension, alone or in combination with other agents [1] . After oral administration, losartan is almost completely absorbed and extensively metabolized to a carboxylic acid derivative, EXP-3174, mainly by cytochrome P450 (CYP) 2C9 and 3A4 [2] . EXP-3174 is a major active metabolite in both rats and humans and is a more potent inhibitor of angiotensin II receptor than losartan, with high-affinity receptor specificity [3] . Losartan has also been reported to be a substrate of P-glycoprotein (P-gp) [4] . Considering that losartan is a substrate of both CYP enzymes and P-gp, the modulation of CYP and P-gp activities may cause significant changes in the pharmacokinetic profiles of losartan and its active metabolite, EXP-3174.Ticlopidine, a potent antiplatelet agent induced by adenosine diphosphate, is used for the treatment of a variety of platelet-dependent disease states [5] . Several papers recommend ticlopidine as a valuable alternative when patients cannot tolerate aspirin [6,7] . It has been reported that ticlopidine causes significant inhibition of several drugs metabolized by the hepatic CYP enzyme system [8,9] .Clinically, losartan and ticlopidine can be prescribed concomitantly for the prevention or therapy of cardiovascular diseases. However, the pharmacokinetic interaction between ticlopidine and losartan in vivo has not yet been reported. Therefore, the present study aimed to evaluate the effect of ticlopidine on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats. The effects of ticlopidine on P-gp, CYP2C9, and 3A4 activities were also evaluated. Materials and methods ChemicalsLosartan, EXP-3174, L-158.809 (internal standard), acetonitrile, methanol, and tert-butylmethylether were purchased from Merck Corporation (Darmstadt, Germany). Ticlopidine was purchased from Sigma-Aldrich Corporation (St Louis, MO, USA). All other chemicals were of reagent grade, and all solvents were of HPLC grade. Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in ratsSi-hyung YANG 1 , Young-ah CHO 2 , Jun-shik CHOI 3, * Aim: Losartan and antiplatelet agent ticlopidine can be prescribed concomitantly for prevention or therapy of cardiovascular diseases. Hence, the effects of ticlopidine on the pharmacokinetics of losartan and its active metabolite EXP-3174 were evaluated in rats. Methods: Ticlopidine (4 or 10 mg/kg po) was administered 30 min before administration of losartan (9 mg/kg po or 3 mg/kg iv). The activity of human CYP2C9 and 3A4 were measured using the CYP inhibition assay kit. The activity of P-gp was evaluated using rhodamine-123 retention assay in MCF-7/ADR cells. Results: Ticlopidine (10 mg/kg) significantly increased the areas under the plasma concentration-time curves (AUCs) and peak plasma concentration (C max ) of oral losartan (9 mg/kg), as well as the AUCs of the active metabolite EXP-3174. Ticlopid...

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The Small Intestine as a Xenobiotic-Metabolizing Organ

Cited by 203 publications

References 72 publications

Vitamin D and colon cancer

Vitamin D and colon cancer

Characterization of Cytochrome P450 Protein Expression along the Entire Length of the Intestine of Male and Female Rats

Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats

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