Increased resistance of peroxisome proliferator-induced hepatic lesions to iron overload in rats

Rao, M. Sambasiva; Subbarao, V.; Reddy, Janardan K.

doi:10.1016/0304-3835(86)90036-4

Cited by 5 publications

(3 citation statements)

References 15 publications

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“…Altered areas (AA) appear first, followed by neoplastic nodules (NN,) and finally hepatocellular carcinomas (HCC) develop. Morphological and phenotypic properties ofthese lesions are well characterized (39)(40)(41). In AA and NN there is increased cellularity, crowding of nuclei, and prominence of nucleoli.…”

Section: Hepatocarcinogenicity Of Peroxisome Proliferatorsmentioning

confidence: 91%

An overview of peroxisome proliferator-induced hepatocarcinogenesis.

Rao

Reddy

1991

Environ Health Perspect

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Peroxisome proliferators are hepatocarcinogens in rats and mice. Chronic administration of these compounds results in the development of altered areas and neoplastic nodules followed by hepatocellular carcinomas. All three types of hepatic lesions do not express y-glutamyltranspeptidase, glutathione 8-transferase-P, and a-fetoprotein and are resistant to iron accumulation after overload. The mechanism by which nongenotoxic peroxisome proliferators induce hepatic tumors is not well understood. It has been proposed that with continuous administration of peroxisome proliferators, liver cells are subjected to persistent oxidative stress resulting from marked proliferation of peroxisomes and a differential increase in the levels of H202 producing (20-to 30-fold) and degrading (2-fold) enzymes. Free oxygen radicals lead to DNA damage (both directly and through lipid peroxidation) and thus may cause initiation and promotion of the carcinogenic process.

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Section: Hepatocarcinogenicity Of Peroxisome Proliferatorsmentioning

confidence: 91%

An overview of peroxisome proliferator-induced hepatocarcinogenesis.

Rao

Reddy

1991

Environ Health Perspect

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“…The 42-day exposure herein actually caused iron loading, as indicated by the percentage increase in total iron (25-86%) exceeding that of the proportion of hepatomegaly (10 -30%). On the other hand, tumors induced by chronic PP administration are strongly resistant to iron accumulation even given very high levels of dietary iron (Rao et al, 1986). Taking together, a time-dependent effect of PP on hepatic iron homeostasis is indicated in that liver iron increases transiently in the initial stage of PPinduced liver hyperplasia preceding the development of hepatocellular carcinomas (HCC).…”

Section: Clofibrate and Liver Iron Accumulationmentioning

confidence: 99%

Role of Hypolipidemic Drug Clofibrate in Altering Iron Regulatory Proteins IRP1 and IRP2 Activities and Hepatic Iron Metabolism in Rats Fed a Low-Iron Diet

Huang

Shaw

2002

Toxicology and Applied Pharmacology

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“…To address the problems of toxicities associated with statins and fibrates, ezetimibe was launched in 2002 as a new drug which inhibits cholesterol absorption in the intestine without affecting the absorption of triglycerides [ 21 ]. Ezetimibe inhibits free cholesterol uptake from the intestine and as such reduces plasma LDLC levels.…”

Section: Introductionmentioning

confidence: 99%

Novel Phenoxazinones as potent agonist of PPAR-α: design, synthesis, molecular docking and in vivo studies

et al. 2018

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BackgroundThe use of statin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for the treatment of dyslipidemia has been associated with dose limiting hepatoxicity, mytotoxicity and tolerability due to myalgias thereby necessitating the synthesis of new drug candidates for the treatment of lipid disorder.MethodsThe reaction of appropriate benzenesulphonamide with substituted phenoxazinone in the presence of phenylboronic acid gave the targeted compounds. The molecular docking study were carried out using autodock tool against peroxisome proliferator activated receptor alpha. The in vivo lipid profile were assayed using conventional methods. The kidney and liver function test were carried out to assess the effect of the derivatives on the organs. The LD50 of the most active derivatives were determined using mice.ResultsThe targeted compounds were successfully synthesized in excellent yields and characterized using spectroscopic techniques. The results of the molecular docking experiment showed that they were good stimulant of peroxisome proliferator activated receptor alpha. Compound 9f showed activity at Ki of 2.8 nM and binding energy of 12.6 kcal/mol. All the compounds tested reduced triglyceride, total cholesterol, low density lipoprotein cholesterol and very low density lipoprotein cholesterol level in the mice model. Some of the reported compounds also increased high density lipoprotein cholesterol level in the mice. The compounds did not have appreciable effect on the kidney and liver of the mice used. The LD50 showed that the novel compounds have improved toxicity profile.ConclusionThe synthesis of fifteen new derivatives of carboxamides bearing phenoxazinone and sulphonamide were successful. The compounds possessed comparable activity to gemfibrozil. The reported compounds had better toxicity profile than gemfibrozil and could serve as a replacement for the statins and fibrate class of lipid agents.

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Increased resistance of peroxisome proliferator-induced hepatic lesions to iron overload in rats

Cited by 5 publications

References 15 publications

An overview of peroxisome proliferator-induced hepatocarcinogenesis.

An overview of peroxisome proliferator-induced hepatocarcinogenesis.

Role of Hypolipidemic Drug Clofibrate in Altering Iron Regulatory Proteins IRP1 and IRP2 Activities and Hepatic Iron Metabolism in Rats Fed a Low-Iron Diet

Novel Phenoxazinones as potent agonist of PPAR-α: design, synthesis, molecular docking and in vivo studies

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