Hepatic expression of cytochrome P450 in Zucker diabetic fatty rats

Park, So Young; Kim, Chung Hyeon; Lee, Ji Yoon; Jeon, Jang Su; Kim, Min Ju; Chae, Song Hee; Kim, Hyoung Chin; Oh, Soo Jin; Kim, Sang Kyum

doi:10.1016/j.fct.2016.08.010

Cited by 19 publications

(14 citation statements)

References 44 publications

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“…Moreover, 5-week-old ZDF rats, but not 11-week-old ZDF rats, showed lower levels of cytochrome b5, CYP2B1, CYP2C11, CYP2E1 and CYP3A2. Consistently, pentoxyresorufin O-depentylation, testosterone 2α-and 16α-hydroxylation, chlorzoxazone 6-hydroxylation, and midazolam 1'-and 4-hydroxylation were decreased only in 5-week-old ZDF rats [55]. Expressions (mRNA and proteins) of CYP3A11/13 and their activities were significantly increased in STZ-induced diabetic C57BLKS/J mice and db/db mice [56].…”

Section: Cyp450smentioning

confidence: 78%

Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance

Yang

Liu

2020

Pharmaceutics

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The pharmacokinetics of a drug is dependent upon the coordinate work of influx transporters, enzymes and efflux transporters (i.e., transporter-enzyme interplay). The transporter–enzyme interplay may occur in liver, kidney and intestine. The influx transporters involving drug transport are organic anion transporting polypeptides (OATPs), peptide transporters (PepTs), organic anion transporters (OATs), monocarboxylate transporters (MCTs) and organic cation transporters (OCTs). The efflux transporters are P-glycoprotein (P-gp), multidrug/toxin extrusions (MATEs), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). The enzymes related to drug metabolism are mainly cytochrome P450 enzymes (CYP450s) and UDP-glucuronosyltransferases (UGTs). Accumulating evidence has demonstrated that diabetes alters the expression and functions of CYP450s and transporters in a different manner, disordering the transporter–enzyme interplay, in turn affecting the pharmacokinetics of some drugs. We aimed to focus on (1) the imbalance of transporter-CYP450 interplay in the liver, intestine and kidney due to altered expressions of influx transporters (OATPs, OCTs, OATs, PepTs and MCT6), efflux transporters (P-gp, BCRP and MRP2) and CYP450s (CYP3As, CYP1A2, CYP2E1 and CYP2Cs) under diabetic status; (2) the net contributions of these alterations in the expression and functions of transporters and CYP450s to drug disposition, therapeutic efficacy and drug toxicity; (3) application of a physiologically-based pharmacokinetic model in transporter–enzyme interplay.

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Section: Cyp450smentioning

confidence: 78%

Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance

Yang

Liu

2020

Pharmaceutics

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“…There are three unique features of the current study: (1) Most of the studies on agerelated changes in hepatic CYPs are performed in mice, (Cui et al 2012;Hart et al 2009;Li et al 2009) this study characterized CYPs and NRs in rats, another commonly-used laboratory animals; (2) Most of the age-related changes in hepatic P450 are focused on the developmental stages to maturation, (Asaoka et al 2010;Bondarenko et al 2016;Cui et al 2012;de Zwart et al 2008;Kilanowicz et al 2015;Park et al 2016) and this study covered the whole life span, and (3) this study extended our efforts to characterize age-and sex-related changes in hepatic drug transporters Zhu et al 2017) and defense mechanisms. Xu et al 2018a;Xu et al 2018b) P450-1 family CYP1 family is responsible for activation of toxicants and drugs.…”

Section: Discussionmentioning

confidence: 99%

“…For example, CYPs expression can be affected by hormones (Daskalopoulos et al 2012), cytokines (Kot & Daujat-Chavanieu 2018), pregnancy, (He et al 2005) sex, (Agrawal & Shapiro 2003;Das et al 2014) and age. CYPs are subjected to agedependent changes in cell differentiation (Czekaj et al 2010) and epigenetic regulation, (Li et al 2009) and age-related metabolic syndrome, (Bondarenko et al 2016) kidney diseases, (Velenosi et al 2012) diabetes, (Park et al 2016) nonalcoholic steatohepatitis, (Li et al 2017) virus hepatitis, and cirrhosis. (Kirby et al 1996) Age of animals greatly affects drug metabolism, (Durnas et al 1990) alters pharmacokinetics of xenobiotics, (Matalova et al 2016;Shi & Klotz 2011) and thus alters the sensitivity to drugs and toxicants such as acetaminophen, (Mach et al 2014) isoniazid, (Mach et al 2016) aflatoxin B1, (Kirby et al 1996;Wang et al 2018) and thioacetamide.…”

Section: Introductionmentioning

confidence: 99%

Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats

Xie

et al. 2019

Preprint

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Cytochrome P450s (CYPs) are phase-I metabolic enzymes playing important roles in drug metabolism, dietary chemicals and endogenous molecules. Age is a key factor influencing P450s expression. Thus, age-related changes of CYP 1-4 families and bile acid homeostasis-related CYPs, the corresponding nuclear receptors and a few phase-II genes were examined. Livers from male Sprague-Dawley rats at fetus (-2 d), neonates (1, 7, and 14 d), weanling (21 d), puberty (28 and 35 d), adulthood (60 and 180 d), and aging (540 and 800 d) were collected and subjected to qPCR analysis. Liver proteins from 14, 28, 60, 180, 540 and 800 days of age were also extracted for selected protein analysis by Western-blot. In general, there were three patterns of their expression: Some of the drug-metabolizing enzymes and related nuclear receptors were low in fetal and neonatal stage, increased with liver maturation and decreased quickly at aging (AhR, Cyp1a1, Cyp2b1, Cyp2b2, Cyp3a1, Cyp3a2, Ugt1a2); the majority of P450s (Cyp1a2, Cyp2c6, Cyp2c11, Cyp2d2, Cyp2e1, CAR, PXR, FXR, Cyp7a1, Cyp7b1. Cyp8b1, Cyp27a1, Ugt1a1, Sult1a1, Sult1a2) maintained relatively high levels throughout the adulthood, and decreased at 800 days of age; and some had an early peak between 7 and 14 days (CAR, PXR, PPARα, Cyp4a1, Ugt1a2). The protein expression of CYP1A2, CYP2B1, CYP2E1, CYP3A1, CYP4A1, and CYP7A1 corresponded the trend of mRNA changes. In summary, this study characterized three expression patterns of 16 CYPs, 5 nuclear receptors, and 4 phase-II genes during development and aging in rat liver, adding to our understanding of age-related CYP expression changes and age-related disorders.

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“…Cyp3a2 and Cyp2c13 are important drug metabolic enzymes in rat livers. Cyp3a2 activity was suppressed and appeared in cases of acute formaldehyde poisoning, 18 5 week-old Zucker fatty diabetic rats, 19 and human immunodeciency virus-infected rats. 20 One previous study has shown that CYP2C13 was absent in male hyperlipidaemic Sprague-Dawley rats.…”

Section: Common Pathways Analysismentioning

confidence: 98%

High throughput metabolomics-proteomics investigation on metabolic phenotype changes in rats caused byRadix Scrophulariaeusing ultra-performance liquid chromatography with mass spectrometry

Lü

Zhang

et al. 2019

RSC Adv.

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Radix Scrophulariae, a traditional Chinese herb, is used to treat various diseases, including H 2 O 2 -induced apoptosis in cardiomyocytes, HaCaT cells, hyperuricaemia, and depression. This study screened metabolites, proteins and common pathways to better understand both the therapeutic effects and side effects of this herb. Methods: Untargeted metabolomics based on UPLC-TOF-MS, coupled with proteomics based on nano-UPLC-Q-Exactive-MS/MS, were used to investigate the effects of R. Scrophulariae in rats. Fifty-one identified metabolites in urine samples and 76 modulated proteins in liver tissue were potential biomarkers for R. Scrophulariae treatment. The biomarkers and common pathways involved were steroid hormone biosynthesis, drug metabolism-cytochrome p450, drug metabolism-other enzymes, pentose and glucuronate interconversions, and starch and sucrose metabolism. Some biomarkers were beneficial for treating diseases such as cancer, tuberculosis and isovaleric acidaemia, while other biomarkers caused side effects.Metabolomic and proteomic analyses of R. Scrophulariae-treated rats provided valuable information on the biological safety and efficacy of using R. Scrophulariae clinically.

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Hepatic expression of cytochrome P450 in Zucker diabetic fatty rats

Cited by 19 publications

References 44 publications

Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance

Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance

Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats

High throughput metabolomics-proteomics investigation on metabolic phenotype changes in rats caused byRadix Scrophulariaeusing ultra-performance liquid chromatography with mass spectrometry

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