Hepatic early inflammation induces downregulation of hepatic cytochrome P450 expression and metabolic activity in the dextran sulfate sodium-induced murine colitis.
Kusunoki Y1, Ikarashi N1, Hayakawa Y1, Ishii M1, Kon R1, Ochiai W1, Machida Y2, Sugiyama K3.Author information 1Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.2Division of Applied Pharmaceutical Education and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.3Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. Electronic address: sugiyama@hoshi.ac.jp.AbstractUlcerative colitis (UC) patients may have increased concentrations of drugs in their blood. We hypothesized that this response is mainly due to a decrease in the expression and activity of the drug-metabolizing enzyme, cytochrome P450 (CYP), in the liver. In this study, we have tried to demonstrate the hypothesis. UC was induced in mice by treatment with dextran sulfate sodium (DSS) solution. The mRNA and protein expression levels of CYP, inflammatory cytokine levels, and the metabolic activity of CYP3A in the liver were measured. The nuclear translocations of nuclear factor kappa B (NF-κB), pregnane X receptor (PXR), and constitutive androstane receptor (CAR) were analyzed. The levels of hepatic inflammatory cytokines increased in the DSS-treated group. The hepatic mRNA and protein expression of CYP (CYP1A, CYP2C, CYP2D, CYP2E, and CYP3A) and the CYP3A metabolic activity significantly decreased compared to the control group. Hepatic NF-κB nuclear translocation significantly increased in the DSS-treated group. In contrast, the nuclear translocations of PXR and CAR were decreased. Lipopolysaccharides from inflammatory sites in the colon induce hepatic inflammation in DSS-induced murine colitis. This inflammation then causes an increase in the nuclear translocation of hepatic NF-κB and a decrease in the nuclear translocation of PXR and CAR, resulting in the decreased expression and activities of CYP. The results of this study indicated that at the onset of UC, the decreased activity of hepatic CYP causes an increase in the concentrations of drugs in the blood, leading to an increase in the incidence of adverse reactions.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.Eur J Pharm Sci.2014 Apr 11;54:17-27. doi: 10.1016/j.ejps.2013.12.019. Epub 2014 Jan 8.
Ulcerative colitis (UC) patients may have increased concentrations of drugs in their blood. We hypothesized that this response is mainly due to a decrease in the expression and activity of the drug-metabolizing enzyme, cytochrome P450 (CYP), in the liver. In this study, we have tried to demonstrate
Contribution of cytochrome P450 isoforms to gliquidone metabolism in rats and human.
He F, Li Y, Zeng C, Xia C, Xiong Y, Zhang H, Huang S, Liu M.Author information Clinical Pharmacology Institute, Nanchang University , Nanchang , R.P. China .AbstractAbstract 1. Gliquidone, a second generation sulfonylurea, is a widely used oral antidiabetic drug. Due to the differences in its rate of metabolism, gliquidone shows inter-subject variability in pharmacokinetic and pharmacodynamic profiles. 2. Cytochrome P450 (CYP450) isoforms are involved in the metabolism of a majority of drugs in clinical use and plays a significant role in reducing possible drug interactions. This research aimed to systematically study the contribution of various human CYP450 isoforms to gliquidone metabolism in vitro in rats and human. 3. In rat liver microsomes, gliquidone was metabolized mainly by the most abundant CYP2C. The other isoforms involved in the metabolism included CYP3A, CYP2D, CYP1A and CYP2E. 4. Further investigation of rat recombinant enzymes showed that CYP3A1 and CYP2C11 played a major role in gliquidone metabolism in vitro, while CYP2D1, CYP1A2 and CYP2E1 were also involved. 5. But the metabolism of gliquidone in the human liver microsomes was mainly mediated by CYP3A4. The other isoforms involved in this process were CYP2C9, CYP2C19 and CYP2D6. 6. The further study of human recombinant enzymes demonstrated that CYP3A4 was the principal isoform enzyme for the metabolism of gliquidone. The intrinsic clearance (Vmax/Km) of CYP3A4 during gliquidone metabolism was 3-12 times greater than that of other CYP450 isoforms including CYP2C9, CYP2D6 and CYP2C19. 7. These findings may assist in valuable prediction of potential interactions of gliquidone with other drugs that are CYP3A4 inhibitors or inducers and help to design more efficacious and safer pharmacotherapy for patients of diabetes mellitus.
Xenobiotica; the fate of foreign compounds in biological systems.Xenobiotica.2014 Mar;44(3):229-34. doi: 10.3109/00498254.2013.831957. Epub 2013 Aug 29.
Abstract 1. Gliquidone, a second generation sulfonylurea, is a widely used oral antidiabetic drug. Due to the differences in its rate of metabolism, gliquidone shows inter-subject variability in pharmacokinetic and pharmacodynamic profiles. 2. Cytochrome P450 (CYP450) isoforms are involved in
Wang X1, Li J2, Dong G3, Yue J4.Author information 1Department of Pharmacology, School of Medical Sciences, Wuhan University, No. 185 East Lake Road, Wuhan 430071, China; Department of Pharmacy, Wuhan Puren Hospital, Wuhan 430081, China.2Department of Pharmacology, School of Medical Sciences, Wuhan University, No. 185 East Lake Road, Wuhan 430071, China.3Baotou Teachers' College, Inner Mongolia University of Science & Technology, Baotou 014030, China.4Department of Pharmacology, School of Medical Sciences, Wuhan University, No. 185 East Lake Road, Wuhan 430071, China. Electronic address: yuejiang@whu.edu.cn.AbstractCYP2D6, one of the major cytochrome P450 isoforms present in the human brain, is associated with the incidence and prevalence of central nervous system (CNS) diseases. Human CYP2D6 and rat CYP2D are involved in the metabolism of various neurotransmitters and neurosteroids. Brain CYP2D can be regulated by endogenous steroids, including sex hormones. The alteration of CYP2D-mediated metabolism induced by endogenous steroids may cause changes in sensitivity to environmental and industrial toxins and carcinogens as well as physiological and pathophysiological processes controlled by biologically active compounds. This review summarizes the current knowledge regarding the distribution, endogenous substrates, and regulation of brain CYP2D.
European journal of pharmacology.Eur J Pharmacol.2014 Feb 5;724C:211-218. doi: 10.1016/j.ejphar.2013.12.025. Epub 2013 Dec 24.
CYP2D6, one of the major cytochrome P450 isoforms present in the human brain, is associated with the incidence and prevalence of central nervous system (CNS) diseases. Human CYP2D6 and rat CYP2D are involved in the metabolism of various neurotransmitters and neurosteroids. Brain CYP2D can be regulat
Important and critical scientific aspects in pharmacogenomics analysis : lessons from controversial results of tamoxifen and CYP2D6 studies (Special Section on Pharmacogenomics : recent advances and future directions)