ABSTRACT
The aim of this study is to evaluate the efficacy of total saponins of Dioscorea (TSD), an extract of the Chinese herbal Bi Xie, on hyperuricemia and to elucidate the underlying mechanisms. The rat hyperuricemia model was established by administration of adenine. Thirty-two rats were randomly allocated into 4 groups: model group, low/high-dose TSD-treated groups, and allopurinol-treated group. Meanwhile, 8 rats were used as normal controls. Serum uric acid (UA), blood urea nitrogen (BUN), serum creatinine (Scr), and organic anion transporting polypeptide 1A1 (OATP1A1) levels were measured. Comparison between the model group and treatment (allopurinol and TSD) groups showed the serum UA levels were significantly decreased in treatment groups. TSD had similar effects to allopurinol. It was found that the OATP1A1 protein expression levels in treatment groups were higher than in model group and normal controls. And different from the allopurinol-treated groups, TSD-treated group had elevated OATP1A1 expression levels in the stomach, liver, small intestine and large intestine tissues. It was suggested that TSD may facilitate the excretion of UA and lower UA levels by up-regulating OATP1A1 expression.
Subject(s)
Animals , Male , Rats , Creatinine , Blood , Dioscorea , Chemistry , Drugs, Chinese Herbal , Pharmacology , Therapeutic Uses , Hyperuricemia , Drug Therapy , Intestines , Metabolism , Liver , Metabolism , Organic Anion Transporters, Sodium-Independent , Genetics , Metabolism , Rats, Sprague-Dawley , Saponins , Pharmacology , Therapeutic Uses , Stomach , Metabolism , Up-Regulation , Uric Acid , BloodSubject(s)
Humans , Male , Female , Aged , Aged, 80 and over , Clarithromycin/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Cytochrome P-450 CYP3A Inhibitors/adverse effects , Pyrimidines/metabolism , Pyrimidines/therapeutic use , Pyrimidines/pharmacokinetics , Rhabdomyolysis/chemically induced , Sulfonamides/metabolism , Sulfonamides/therapeutic use , Sulfonamides/pharmacokinetics , Fatty Acids, Monounsaturated/metabolism , Fatty Acids, Monounsaturated/therapeutic use , Fatty Acids, Monounsaturated/pharmacokinetics , Pravastatin/metabolism , Pravastatin/therapeutic use , Pravastatin/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Organic Anion Transporters , Organic Anion Transporters, Sodium-Independent/antagonists & inhibitors , Liver-Specific Organic Anion Transporter 1 , Drug Interactions , Acute Kidney Injury/chemically induced , Rosuvastatin Calcium , Fluorobenzenes/metabolism , Fluorobenzenes/therapeutic use , Fluorobenzenes/pharmacokinetics , Solute Carrier Organic Anion Transporter Family Member 1B3 , Fluvastatin , Hyperkalemia/chemically induced , Indoles/metabolism , Indoles/therapeutic use , Indoles/pharmacokineticsABSTRACT
<p><b>OBJECTIVE</b>To study the effect of Zhusha Anshen pill, cinnabar, HgS, HgCl2 and MeHg on the gene expression of renal transporters in mice.</p><p><b>METHOD</b>Healthy male mice were given equivalent physiological saline, Zhusha Anshen pill (1.8 g · kg(-1), containing 0.17 g · kg(-1) of mercury), cinnabar (0.2 g · kg(-1), containing 1.7 g · kg(-1) of mercury), high dose cinnabar (2 g · kg(-1), containing 1.7 g · kg(-1) of mercury), HgS (0.2 g · kg(-1), containing 0.17 g · kg(-1) of mercury), HgCl2 (0.032 g · kg(-1), containing 0. 024 g · kg(-1) of mercury), MeHg (0.026 g · kg(-1), containing 0.024 g · kg(-1) of mercury), once daily, for 30 d, measuring body mass gain. 30 days later, the mice were sacrificed. The mercury accumulation in kidneys was detected with atomic fluorescence spectrometer. Expressions of Oat1, Oat2, Oat3, Mrp2, Mrp4, Urat1 were detected with RT-PCR.</p><p><b>RESULT</b>Compared with the normal control group, a significant accumulation of Hg in kidney in HgCl2 and MeHg groups was observed (P <0.05), but these changes were not found in other groups. Compared with normal control group, mRNA expressions of Oat1 and Oat2 were evidently lower in HgCl2 and MeHg groups, but mRNA expressions of Mrp2 were apparently higher in HgCl2 group (P <0.05), mRNA expression of Mrp4 was significant higher in HgCl2 and MeHg groups, and mRNA expression of Urat1 was apparently lower in MeHg group.</p><p><b>CONCLUSION</b>HgCl2 and MeHg groups show significant difference from the normal group in mercury accumulation in kidneys and gene expression of kidney transporters, but with no difference between other groups and the normal group. Compared with HgCl2 and MeHg, cinnabar and its compounds could cause lower renal toxicity to mice.</p>
Subject(s)
Animals , Male , Mice , Carrier Proteins , Genetics , Drugs, Chinese Herbal , Toxicity , Gene Expression , Kidney , Metabolism , Mercuric Chloride , Toxicity , Mercury Compounds , Toxicity , Methylmercury Compounds , Toxicity , Multidrug Resistance-Associated Proteins , Genetics , Organic Anion Transport Protein 1 , Genetics , Organic Anion Transporters, Sodium-Independent , GeneticsABSTRACT
Liver is regarded as one of the most important organs for drug clearance in the body, which mediates both the metabolism and biliary excretion of drugs. Transporters are a class of functional membrane proteins and control the movement of substances into or out of cells. Transporters, which are extensively expressed in the liver, play important roles in the drug hepatic disposition by regulating the uptake of drugs from blood into hepatocytes or the efflux of drugs and their metabolites into bile. In this review, the localization, functions and substrate selectivity of the major transporters in the liver will be summarized, and the impacts of these transporters on drug hepatic disposition, the potential drug-drug interactions as well as their genetic polymorphisms will also be reviewed.
Subject(s)
Humans , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters , Genetics , Metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Genetics , Metabolism , Bile , Metabolism , Biological Transport , Drug Interactions , Liver , Metabolism , Membrane Transport Proteins , Genetics , Metabolism , Metabolic Clearance Rate , Multidrug Resistance-Associated Proteins , Genetics , Metabolism , Neoplasm Proteins , Genetics , Metabolism , Organic Anion Transporters , Genetics , Metabolism , Organic Anion Transporters, Sodium-Dependent , Metabolism , Organic Anion Transporters, Sodium-Independent , Genetics , Metabolism , Organic Cation Transport Proteins , Genetics , Metabolism , Pharmacokinetics , Polymorphism, Genetic , Symporters , MetabolismABSTRACT
This paper reports on issues relating to the optimal use of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging (Gd-EOB-DTPA MR imaging) together with the generation of consensus statements from a working group meeting, which was held in Seoul, Korea (2010). Gd-EOB-DTPA has been shown to improve the detection and characterization of liver lesions, and the information provided by the hepatobiliary phase is proving particularly useful in differential diagnoses and in the characterization of small lesions (around 1-1.5 cm). Discussion also focused on advances in the role of organic anion-transporting polypeptide 8 (OATP8) transporters. Gd-EOB-DTPA is also emerging as a promising tool for functional analysis, enabling the calculation of post-surgical liver function in the remaining segments. Updates to current algorithms were also discussed.
Subject(s)
Humans , Algorithms , Contrast Media , Diagnosis, Differential , Gadolinium DTPA , Liver Diseases/diagnosis , Liver Function Tests , Magnetic Resonance Imaging , Organic Anion Transporters, Sodium-Independent/metabolism , Postoperative Complications/diagnosis , Practice Guidelines as TopicABSTRACT
OATP1B3, a member of SLC superfamily, is specifically expressed on the sinusoidal membrane of hepatocytes and is considered to be important in hepatic drug elimination. The overexpression of OATP1B3 was found recently in tumor tissues such as prostate, colon, and pancreatic tumors. Sequence variations in SLCO1B3 gene, such as SNPs, have been described and a common haplotype consisting of 334T>G and 699G>A SNPs is related to altered transport characteristics of OATP1B3. OATP1B3 is of relevance to drug metabolism through affecting alteration of hepatic concentration of endo- and xenobiotic compounds that interact with nuclear receptors such as PXR and CAR, and thereby directly alter the extent of target gene transcription, including major CYP isoenzymes such as CYP3A4. This review will provide an overview of substrates and inhibitors of OATP1B3 and subsequently to assess the effect of genetic mutation on transport activity. The studies linking OATP1B3 with cancer clinical outcomes are also discussed in this review.