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Bile acid homeostasis in female mice deficient in Cyp7a1 and Cyp27a1

Acta Pharmaceutica Sinica B 2021年第12期11卷 3847-3856页

作者： Daniel Rizzolo Bo Kong Rulaiha E.Taylora Anita Brinker Michael Goedken Brian Buckley Grace L.Guo Department of Pharmacology and Toxicology School of PharmacyRutgers UniversityPiscatawayNJ 08854USA Environmental and Occupational Health Institute Rutgers UniversityPiscatawayNJ 08854USA Office of Research and Economic Development Research Pathology ServicesRutgers UniversityPiscatawayNJ 08854USA Rutgers Center of Lipid Research Rutgers UniversityNew BrunswickNJ 08901USA Department of Veterans Affairs New Jersey Health Care System East OrangeNJ 07018USA

Bile acids(BAs) are amphipathic molecules important for metabolism of cholesterol,absorption of lipids and lipid soluble vitamins,bile flow,and regulation of gut microbiome.There are over 30 different BA species known to exist in humans and mice,which are endogenous modulators of at least 6 different membrane or nuclear receptors.This diversity of ligands and receptors play important roles in health and disease;however,the full functions of each individual BA in vivo remain unclear.We generated a mouse model lacking the initiating enzymes,CYP7 A1 and CYP27 A1,in the two main pathways of BA synthesis.Because females are more susceptible to BA related diseases,such as intrahepatic cholestasis of pregnancy,we expanded this model into female mice.The null mice of Cyp7 a1 and Cyp27 a1 were crossbred to create double knockout(DKO) mice.BA concentrations in female DKO mice had reductions in serum(63%),liver(83%),gallbladder(94%),and small intestine(85%),as compared to WT mice.Despite low BA levels,DKO mice had a similar expression pattern to that of WT mice for genes involved in BA regulation,synthesis,conjugation,and transport.Additionally,through treatment with a synthetic FXR agonist,GW4064,female DKO mice responded to FXR activation similarly to WT mice.

关键词： Bile acids Farnesoid X receptor Female Fibroblast growth factor 15 CYP7A1 CYP27A1

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Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3869-3878页

作者： Joseph L.Jilek Kayla L.Frost Kevyn A.Jacobus Wenxi He Erica L.Toth Michael Goedken Nathan J.Cherrington Department of Pharmacology&Toxicology College of PharmacyUniversity of ArizonaTucsonAZ 85724USA Rutgers Translational Sciences Rutgers UniversityPiscatawayNJ 08901USA

Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions.Cisplatin(CDDP)elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion.Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis(NASH),however,associated changes to substrate toxicity is unknown.To test this,a methionine-and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics,transporter expression,and toxicity.NASH rats administered CDDP(6 mg/kg,i.p.)displayed 20%less nephrotoxicity than healthy rats.Likewise,CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min,renal secretion decreased from 6.23 to 2.80 mL/min,and renal CDDP accumulation decreased by 15%,relative to healthy rats.Renal copper transporter-1 expression decreased,and organic cation transporter-2 and ATPase copper transporting protein-7 b increased slightly,reducing CDDP secretion.Hepatic CDDP accumulation increased 250%in NASH rats relative to healthy rats.Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats,although no drug-related toxicity was observed.These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance,which may alter nephrotoxicity.

关键词： Nonalcoholic steatohepatitis NASH Cisplatin Drug transporter Nephrotoxicity

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Up-regulation of NAD(P)H quinone oxidoreductase 1 during human liver injury

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World Journal of Gastroenterology 2006年第12期12卷 1937-1940页

作者： Lauren M Aleksunes José EManautou Michael Goedken University of Connecticut Department of Pharmaceutical SciencesUnit 3092StorrsCTUnited States University of Connecticut Department of PathobiologyUnit 3089StorrsCTUnited States

瞄准：为了调查 NAD (P) H 五人一组一氧化还原酶的表示和活动，(NQO1 ) 1 由于 acetaminophen (APAP ) 在与肝从病人获得的人的肝标本损坏服药过量或主要胆汁性肝硬变(PBC ) 。方法：NQO1 活动从正常， APAP 和 PBC 肝标本在 cytosol ... 详细信息

瞄准：为了调查 NAD (P) H 五人一组一氧化还原酶的表示和活动，(NQO1 ) 1 由于 acetaminophen (APAP ) 在与肝从病人获得的人的肝标本损坏服药过量或主要胆汁性肝硬变(PBC ) 。方法：NQO1 活动从正常， APAP 和 PBC 肝标本在 cytosol 被决定。西方的污点和免疫组织化学的染色被用来对 NQO1 用特定的抗体决定 NQO1 表示的模式。结果：NQO1 蛋白质在正常的人的肝是很低的。在 APAP 和 PBC 肝，有西方的污点上的 NQO1 蛋白质层次的强壮的正式就职。相应地，酶活动的重要起来规定(16-fold, 和 22 褶层， P< 0.05 ) 也分别地在 APAP 和 PBC 肝被观察。Immunohistochemical 分析加亮在 APAP 和 PBC 肝染色的 NQO1 的损害特定的模式。结论：这些数据证明那 NQO1 蛋白质和活动显著地在 APAP 服药过量和 PBC 期间在人的肝被导致。这 cytoprotective 酶的起来规定可以代表适应压力回答由除去限制进一步的疾病前进反应种类。

关键词：氧化还原酶肝损伤醋氨酚肝硬化

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