(bilirubin) articles in PubMed
- Inhibition of Hepatobiliary Transport Activity by the Antibacterial Agent Fusidic Acid: Insights into Factors Contributing to Conjugated Hyperbilirubinemia / Cholestasis. [Journal Article]
- Chem Res Toxicol 2016 Sep 27CR
- Conjugated hyperbilirubinemia accompanied by cholestasis is a frequent side effect during chronic treatment with the antimicrobial agent fusidic acid. Previous studies from our laboratory, addressing...
Conjugated hyperbilirubinemia accompanied by cholestasis is a frequent side effect during chronic treatment with the antimicrobial agent fusidic acid. Previous studies from our laboratory, addressing mechanisms of musculoskeletal toxicity arising from co-administration of fusidic acid with statins, demonstrated the ability of fusidic acid to potently inhibit human organic anion transporting polypeptides OATP1B1 (IC50 = 1.6 μM) and OATP1B3 (IC50 = 2.5 μM), which are responsible for the uptake-limited clearance of statins as well as bilirubin glucuronide conjugates. In the present work, inhibitory effects of fusidic acid were characterized against additional human hepatobiliary transporters (Na+/taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP) and multidrug resistance-associated proteins MRP2 and MRP3) as well as uridine glucuronosyl transferase (UGT1A1), which mediate the disposition of bile acids and bilirubin (and its conjugated metabolites). Fusidic acid demonstrated concentration-dependent inhibition of human NTCP- and BSEP-mediated taurocholic acid transport with IC50 values of 44 and 3.8 μM, respectively. Inhibition of BSEP activity by fusidic acid was also consistent with the potent disruption of cellular biliary flux (AC50 = 11 μM) in the hepatocyte imaging assay technology (HIAT) assay, with minimal impact on other toxicity endpoints (e.g., cytotoxicity, mitochondrial membrane potential, reactive oxygen species generation, glutathione depletion, etc.). Fusidic acid also inhibited UGT1A1-catalyzed β-estradiol glucuronidation activity in human liver microsomes with an IC50 value of 16 µM. Fusidic acid did not demonstrate any significant inhibition of ATP-dependent LTC4 transport (IC50's > 300 μM) in human MRP2 or MRP3 vesicles. R-values, which reflect maximal in vivo inhibition, were estimated from a static mathematical model by taking into consideration the IC50 values generated in the various in vitro assays and clinically efficacious unbound fusidic acid concentrations. The magnitude of in vivo interaction (R-values) resulting from inhibition of OATP1B1, UGT1A1, NTCP, and BSEP transport was ~ 1.9-2.6, 1.1-1.2, 1.0-1.1, and 1.4-1.7, respectively, which is indicative of some degree of inherent toxicity risk particularly via inhibition of OATP and BSEP. Collectively, these observations indicate that inhibition of human BSEP by fusidic acid could affect bile acid homeostasis resulting in cholestatic hepatotoxicity in the clinic. Lack of direct inhibitory effects on MRP2 transport by fusidic acid suggests that conjugated hyperbilirubinemia does not arise via interference in MRP2-mediated biliary disposition of bilirubin glucuronides. Instead, it is possible that elevation in the level of bilirubin conjugates in blood is mediated through inhibition of hepatic OATPs, which are responsible for their reuptake and/or downregulation of MRP2 transporter as a consequence of cholestatic injury.
- Assessment of the Albumin-Bilirubin (ALBI) Grade as a Prognostic Indicator for Hepatocellular Carcinoma Patients Treated with Radioembolization. [Journal Article]
- Int J Radiat Oncol Biol Phys 2016 Oct 1; 96(2S):E220IJ
- Assessment of Hepatic Function Decline After Stereotactic Body Radiation Therapy for Primary Liver Tumors Using the Albumin-Bilirubin (ALBI) Score. [Journal Article]
- Int J Radiat Oncol Biol Phys 2016 Oct 1; 96(2S):E203-E204IJ
- Clinical characteristics of drug-induced liver injury and primary biliary cirrhosis. [Journal Article]
- World J Gastroenterol 2016 Sep 7; 22(33):7579-86WJ
- CONCLUSIONS: Although DILI and PBC share some similar laboratory tests (biochemical and immunological indexes) and pathological findings, they also show some distinct characteristics, which are helpful to the differential diagnosis of the two diseases.
- Are atherosclerotic risk factors associated with a poor prognosis in patients with hyperuricemic acute heart failure? The evaluation of the causal dependence of acute heart failure and hyperuricemia. [Journal Article]
- Heart Vessels 2016 Sep 26HV
- Atherosclerosis induces the elevation of uric acid (UA), and an elevated UA level is well known to lead to a poor prognosis in patients with acute heart failure (AHF). However, the prognostic value o...
Atherosclerosis induces the elevation of uric acid (UA), and an elevated UA level is well known to lead to a poor prognosis in patients with acute heart failure (AHF). However, the prognostic value of atherosclerotic risk factors in hyperuricemic AHF patients remains to be elucidated. The data from 928 patients who were admitted to the intensive care unit (ICU) at Nippon Medical School Chiba Hokusoh Hospital between January 2001 and December 2014, and whose serum UA levels were measured were screened. A total of 394 AHF patients with hyperuricemia were enrolled in this study. The patients were assigned to a low-risk group (≤1 atherosclerosis risk factor) and a high-risk group (≥2 atherosclerosis risk factors) according to their number of risk factors. The patients in the low-risk group were more likely to have dilated cardiomyopathy, clinical scenario 3 than those in the high-risk group. The serum total bilirubin, blood urea nitrogen, C-reactive protein, and brain-type natriuretic peptide levels were significantly higher in the low-risk group than the high-risk group (p < 0.001, p = 0.005, p = 0.003, and p = 0.008, respectively). A multivariate Cox regression model revealed that the number of risk factors (number = 1, HR (hazard ratio) 0.243, 95 % CI 0.096-0.618, p = 0.003; number = 2, HR 0.253, 95 % CI 0.108-0.593, p = 0.002; number ≥3, HR 0.209, 95 % CI 0.093-0.472, p < 0.001), eGFR (per 1.0 mmol/l increase) (HR 0.977, 95 % CI 0.961-0.994, p = 0.007), and serum UA level (per 1 mg/dl increase) (HR 1.270, 95 % CI 1.123-1.435, p < 0.001) was an independent predictor of 1-year mortality. The prognosis, including all-cause death and HF events, was significantly poorer among the low-risk patients than among the high-risk patients. Atherosclerotic risk factors were not associated with a poor prognosis in patients with hyperuricemic AHF.
- Two-hourly versus 3-hourly feeding for very low birthweight infants: a randomised controlled trial. [Journal Article]
- Arch Dis Child Fetal Neonatal Ed 2016 Sep 26AD
- CONCLUSIONS: 3-hourly feeding was comparable with 2-hourly feeding to achieve full enteral feeding without any evidence of increased adverse events.
- Characterization of heme oxygenase and biliverdin reductase gene expression in zebrafish (Danio rerio): Basal expression and response to pro-oxidant exposures. [Journal Article]
- Toxicol Appl Pharmacol 2016 Sep 23TA
- While heme is an important cofactor for numerous proteins, it is highly toxic in its unbound form and can perpetuate the formation of reactive oxygen species. Heme oxygenase enzymes (HMOX1 and HMOX2)...
While heme is an important cofactor for numerous proteins, it is highly toxic in its unbound form and can perpetuate the formation of reactive oxygen species. Heme oxygenase enzymes (HMOX1 and HMOX2) degrade heme into biliverdin and carbon monoxide, with biliverdin subsequently being converted to bilirubin by biliverdin reductase (BVRa or BVRb). As a result of the teleost-specific genome duplication event, zebrafish have paralogs of hmox1 (hmox1a and hmox1b) and hmox2 (hmox2a and hmox2b). Expression of all four hmox paralogs and two bvr isoforms were measured in adult tissues (gill, brain and liver) and sexually dimorphic differences were observed, most notably in the basal expression of hmox1a, hmox2a, hmox2b and bvrb in liver samples. hmox1a, hmox2a and hmox2b were significantly induced in male liver tissues in response to 96h cadmium exposure (20μM). hmox2a and hmox2b were significantly induced in male brain samples, but only hmox2a was significantly reduced in male gill samples in response to the 96h cadmium exposure. hmox paralogs displayed significantly different levels of basal expression in most adult tissues, as well as during zebrafish development (24 to 120 hpf). Furthermore, hmox1a, hmox1b and bvrb were significantly induced in zebrafish eleutheroembryos in response to multiple pro-oxidants (cadmium, hemin and tert-butylhydroquinone). Knockdown of Nrf2a, a transcriptional regulator of hmox1a, was demonstrated to inhibit the Cd-mediated induction of hmox1b and bvrb. These results demonstrate distinct mechanisms of hmox and bvr transcriptional regulation in zebrafish, providing initial evidence of the partitioning of function of the hmox paralogs.
- Beneficial effects of mucous fistula refeeding in necrotizing enterocolitis neonates with enterostomies. [Journal Article]
- J Pediatr Surg 2016 Sep 15JP
- CONCLUSIONS: Mucous fistula refeeding is safe and can decrease risk of anastomotic complication and parental nutrition related cholestasis. It provides both diagnostic and therapeutic value preoperatively and its use should be advocated. Level III Treatment Study in a Case Control Manner.
- Regorafenib Versus Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: A Retrospective Comparison. [Journal Article]
- Clin Colorectal Cancer 2016 Aug 31CC
- CONCLUSIONS: Regorafenib and TAS-102 had similar efficacy but resulted in different toxicities, which could guide the agent choice.
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- Oxidative Stress and Environmental Exposures are Associated with Multiple System Atrophy in Chinese Patients. [Journal Article]
- Can J Neurol Sci 2016; 43(5):703-9CJ
- CONCLUSIONS: Elevated Hcys and decreased high-density lipoprotein cholesterol may be associated with the disease severity of MSA. Environmental exposures such as farming and smoking may contribute to the occurrence but not the progression of MSA.