Characterization of cytochrome P450 enzymes involved in drug oxidations in mouse intestinal microsomes

Emoto, Chie; Yamazaki, Hajime; Yamasaki, S.; Shimada, Tsutomu; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1080/00498250050200104

Cited by 60 publications

(45 citation statements)

References 16 publications

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“…Pooled hepatic microsomes from five mice or rats were prepared according to the method described by Emoto et al (2000). Protein concentrations were determined according to the method of Lowry et al (1951) using bovine serum albumin as the standard.…”

Section: Methodsmentioning

confidence: 99%

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Species Differences in UDP-Glucuronosyltransferase Activities in Mice and Rats

Shiratani

Katoh²,

Nakajima³

et al. 2008

Drug Metab Dispos

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ABSTRACT:UDP-glucuronosyltransferases (UGTs), expressed in various tissues including liver and intestine, catalyze phase II metabolic biotransformation. There is little information on species differences between mice and rats in UGT activities, especially in intestine. The purpose of the present study was to clarify the species differences between mice and rats in UGT activities using duodenal and liver microsomes. For estradiol 3-O-glucuronidation in duodenal microsomes, the kinetic data in mice were fit to the Hill equation. However, the Hill coefficient was low in rats (n ‫؍‬ 1.1), suggesting that rat estradiol 3-O-glucuronidation followed the Michaelis-Menten equation rather than the Hill equation. For 4-nitrophenol (4-NP) O-glucuronidation, the K m values were different between mice and rats. The intrinsic clearance (CL int ) values for mycophenolic acid (MPA) O-and morphine 3-O-glucuronidation in male mouse duodenum were 3-and 17-fold lower than those in rat, respectively. In male liver, the CL int values for 4-NP O-, propofol O-, MPA O-, and morphine 3-O-glucuronidation and the CL max value for 4-methylumbelliferone O-glucuronidation in mice were higher than those in rats. The CL max value for estradiol 3-O-glucuronidation in mice was lower than that in rats. Also, there were strain differences among C57BL/6J, BALB/c, C3H/HeJ, DBA/2, ddY, and ICR mice in UGT activities in duodenum. We clarified that the species differences in UGT activity evaluated by the CL int or CL max values in liver and duodenum varied according to the substrate.

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Section: Methodsmentioning

confidence: 99%

“…Pooled duodenal, jejunal, iliac, and colonic microsomes from five mice or rats were prepared according to the method of Emoto et al (2000) with slight modifications. Briefly, duodenum, jejunum, ileum, and colon were divided, cut longitudinally, and then washed in ice-cold 1.15% KCl by gentle swirling.…”

Section: Methodsmentioning

confidence: 99%

Species Differences in UDP-Glucuronosyltransferase Activities in Mice and Rats

Shiratani

Katoh²,

Nakajima³

et al. 2008

Drug Metab Dispos

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“…It should be emphasized that in human intestinal mucosa, the members of CYP3A family play the leading role, especially CYP3A4 isoform (Emoto et al 2000), which participates in metabolism of many xenobiotics and drugs and is generally responsible for the biotransformation of more than 50% of clinical pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

Age-related changes in the mRNA levels of CYP1A1, CYP2B1/2 and CYP3A1 isoforms in rat small intestine

Pałasz

Wiaderkiewicz

et al. 2011

Genes Nutr

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It has been established beyond doubt that, as well as the liver, the small intestine is an important site of first-pass metabolism of numerous drugs, food components and toxic xenobiotics. However, there is not much information available about age-dependent changes of intestinal biotransformation pathways. In the present paper, we evaluated the relationships between intestinal cytochrome P450 complex activity and the age of animals. The study was carried out on male Sprague-Dawley rats (n = 5) from 5 age series: 0.5-, 2-, 4-, 20-, and 28 months old. Animals at every age series were divided into 4 groups: control and three groups of rats treated with the CYP450 specific inducers: phenobarbital, b-naphtoflavone and dexamethasone, respectively. RNA was isolated from intestinal mucosa, and then standard RT-PCR was used for the analysis of CYP1A1, CYP2B1/2 and CYP3A1 mRNA expression. Additionally, the activities of NADPH-cytochrome P450 and NADH-cytochrome b 5 reductases in the microsomal fraction were biochemically estimated. The constitutive intestinal CYP1A1 mRNA expression changes during maturation and aging. Inducibility of CYP1A1 gene was evident in intestinal mucosa at 2-, 4-and 20-month-old rats. A similar pattern of changes was observed for CYP2B1/2 isoforms. CYP3A1 mRNA expression was not detected in small intestine of 2-week-old rats. In matured rats, constitutive intestinal CYP3A1 expression was low, although after induction, significant increases in CYP3A1 mRNA amount were noted in aged individuals. Intestinal activity of both analyzed reductases was lowest in immature rats and highest in 28-month-old animals. In conclusion, the activity of cytochrome P450 complex in rat small intestine was not decreased by the aging processes, so the high rate of oxidative metabolic reactions in intestinal mucosa can be maintained till the advanced life stage.

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“…Genes encoding at least eight different mouse CYP3A isozymes have been identified. 19) Therefore, the identification of CYP3A as two bands on the immunoblots suggests the expression of more than one mouse CYP3A isozyme. In this study, the sum of these band intensities was used to evaluate the expression of CYP3A protein.…”

Section: Effect Of Menthol On Cyp3a Expression Level In the Livermentioning

confidence: 99%

Effects of Menthol on the Pharmacokinetics of Triazolam and Phenytoin

Hoshino

Ikarashi

Hirobe

et al. 2015

Biological & Pharmaceutical Bulletin

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We have previously shown that menthol attenuates the anticoagulant effect of warfarin by increasing the expression levels of CYP3A and CYP2C in the liver. This study evaluated the effects of menthol on the pharmacokinetics of the CYP3A substrate triazolam and the CYP2C substrate phenytoin. Menthol was orally administered to mice for 7 d. Twenty-four hours after the administration of menthol, triazolam was orally administered, and the plasma concentration was measured. In addition, the CYP3A metabolic activity for triazolam and the CYP3A expression level in the liver were determined. The effects of menthol on the pharmacokinetics of phenytoin were assessed in the same manner. In the menthol-treated group, the area under the blood concentration-time curve (AUC) of triazolam was lower and its clearance was higher compared with the control group. The CYP3A metabolic activity and CYP3A expression level in the liver were significantly increased in the menthol-treated group compared with the control group. Similarly, the AUC of phenytoin was lower and the hepatic CYP2C expression level was higher in the menthol-treated group. Thus, menthol lowered the plasma concentrations of triazolam and phenytoin when concurrently administered. These effects may be attributed to an increased metabolic activity for these drugs due to the increased expression of CYP3A and CYP2C in the liver.

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Characterization of cytochrome P450 enzymes involved in drug oxidations in mouse intestinal microsomes

Cited by 60 publications

References 16 publications

Species Differences in UDP-Glucuronosyltransferase Activities in Mice and Rats

Species Differences in UDP-Glucuronosyltransferase Activities in Mice and Rats

Age-related changes in the mRNA levels of CYP1A1, CYP2B1/2 and CYP3A1 isoforms in rat small intestine

Effects of Menthol on the Pharmacokinetics of Triazolam and Phenytoin

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