Coincubation of Rat Renal Proximal Tubules with Hepatic Subcellular Fractions Potentiates the Effects of <i>para</i>-Aminophenol

Shao, Rong; Ring, Steven C.; Tarloff, Joan B.

doi:10.1093/toxsci/39.2.101

Cited by 7 publications

(9 citation statements)

References 29 publications

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“…Hepatic mitochondrial, cytosolic, and microsomal fractions were prepared as previously described (14), and the protein concentrations were determined using the Bradford method. Glucose-6-phosphate dehydrogenase (G6PD) (15), fatty acid synthase (FAS) (16), malic enzyme (ME) (17), and phosphatidate phosphohydrolase (PAP) (18) activities were measured as previously described.…”

Section: Hepatic Enzyme Activities Glycogen H 2 O 2 Concentrationmentioning

confidence: 99%

Luteolin Attenuates Hepatic Steatosis and Insulin Resistance Through the Interplay Between the Liver and Adipose Tissue in Mice with Diet-Induced Obesity

et al. 2014

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The flavonoid luteolin has various pharmacological activities. However, few studies exist on the in vivo mechanism underlying the actions of luteolin in hepatic steatosis and obesity. The aim of the current study was to elucidate the action of luteolin on obesity and its comorbidity by analyzing its transcriptional and metabolic responses, in particular the luteolin-mediated cross-talk between liver and adipose tissue in diet-induced obese mice. C57BL/6J mice were fed a normal, high-fat, and high-fat + 0.005% (weight for weight) luteolin diet for 16 weeks. In high fatfed mice, luteolin improved hepatic steatosis by suppressing hepatic lipogenesis and lipid absorption. In adipose tissue, luteolin increased PPARg protein expression to attenuate hepatic lipotoxicity, which may be linked to the improvement in circulating fatty acid (FA) levels by enhancing FA uptake genes and lipogenic genes and proteins in adipose tissue. Interestingly, luteolin also upregulated the expression of genes controlling lipolysis and the tricarboxylic acid (TCA) cycle prior to lipid droplet formation, thereby reducing adiposity. Moreover, luteolin improved hepatic insulin sensitivity by suppressing SREBP1 expression that modulates Irs2 expression through its negative feedback and gluconeogenesis. Luteolin ameliorates the deleterious effects of diet-induced obesity and its comorbidity via the interplay between liver and adipose tissue.Obesity is characterized by excessive fat accumulation and is associated with metabolic complications such as adiposity, dyslipidemia, insulin resistance, and steatohepatitis. The liver is one of the major organs responsible for metabolizing fats from the diet. Dysregulation of lipid metabolism in the liver induces abnormal accumulation of lipids and the subsequent formation of lipid droplets (LDs), known as hepatic steatosis. Hepatic steatosis is common in obese individuals and is strongly linked to insulin resistance (1,2). Adipose tissue is also a critical component of metabolic control and is an endocrine organ that secretes a number of adipokines known to mediate lipid metabolism, inflammation, and insulin sensitivity (3). Although the complex relationship between adiposity and hepatic steatosis has not been completely elucidated, dysregulation of lipid metabolism in the liver and adipose tissue may be involved in the pathogenesis of adiposity as well as its associated metabolic complications. One hypothesis for the explanation of a link between visceral adiposity and hepatic steatosis and insulin resistance is the "portal hypothesis," which proposes that a high rate of lipolysis of the visceral adipose tissue can lead to an increased delivery of free fatty acids (FFAs) to the liver via the portal vein, and that chronic exposure of the liver to elevated FFAs can promote hepatic steatosis and hepatic insulin resistance (4,5). However, it is still unclear how visceral adiposity is associated with hepatic steatosis and insulin resistance, in particular at the level of transcriptional changes that occur in ...

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Section: Hepatic Enzyme Activities Glycogen H 2 O 2 Concentrationmentioning

confidence: 99%

Luteolin Attenuates Hepatic Steatosis and Insulin Resistance Through the Interplay Between the Liver and Adipose Tissue in Mice with Diet-Induced Obesity

et al. 2014

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“…The reported desulfuration of parathion by the rat brain LO [55], oxidation of benzo(a)pyrene (BP) [56], and epoxidation of aflatoxin B 1 [57] by the pulmonary LO lend strong support for this contention. The bioactivation of p-aminophenol, a potent nephrotoxicant, represents another notable example, since neither P-450 [58] nor PGS [59] is appar-CMLS, Cell. Mol.…”

Section: Importance Of Lo-mediated Xenobiotic Metabolismmentioning

confidence: 99%

“…Vol. 58,2001 Review Article 1807 ently responsible for its toxicity. The results of our study [60] suggest that the LO pathway may be the only route that generates GSH-adducts, the presumed ultimate nephrotoxic species from p-aminophenol.…”

Section: Importance Of Lo-mediated Xenobiotic Metabolismmentioning

confidence: 99%

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Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and xenobiotics

Kulkarni¹

2001

CMLS, Cell. Mol. Life Sci.

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Lipoxygenase, a member of the arachidonate cascade enzymes, dioxygenates polyenoic fatty acids to finally yield products with profound and distinct biological activity. This review summarizes the available evidence for another role played by lipoxygenases in the metabolism of endobiotics and xenobiotics. Although other mechanisms exist, a direct hydrogen abstraction by the enzyme and the peroxyl radical-dependent chemical oxidation appear to be central to the co-oxidase activity of lipoxygenases. Besides polyunsaturated fatty acids, H2O2, fatty acid hydroperoxides, and synthetic organic hydroperoxides support the lipoxygenase-catalyzed xenobiotic oxidation. The major reactions documented thus far include oxidation, epoxidation, hydroxylation, sulfoxidation, desulfuration, dearylation, and N-dealkylation. It is noteworthy that lipoxygenases are also capable of glutathione conjugation of certain xenobiotics. The enzyme system appears to be inducible following exposure to chemicals. Lipoxygenases are inhibited by a large number of chemicals, some of which also serve as co-substrates. Available data suggest that lipoxygenases contribute to in vivo metabolism of xenobiotics in mammals.

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“…These observations suggest a possible mechanism by which CAA impairs renal cell function. Depletion of intracellular sulfhydryl (SH) groups is often associated with toxicity by impairment of the cells defense mechanisms against oxidative stress [14,15] . Thus, the interaction of CAA with non-protein sulfhydryl groups (NPSH) could be a mechanism of toxicity.…”

Section: Introductionmentioning

confidence: 99%

Chloroacetaldehyde as a Sulfhydryl Reagent: The Role of Critical Thiol Groups in Ifosfamide Nephropathy

Benesic

Schwerdt

Freudinger

et al. 2006

Kidney Blood Press Res

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Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients.

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Coincubation of Rat Renal Proximal Tubules with Hepatic Subcellular Fractions Potentiates the Effects of para-Aminophenol

Cited by 7 publications

References 29 publications

Luteolin Attenuates Hepatic Steatosis and Insulin Resistance Through the Interplay Between the Liver and Adipose Tissue in Mice with Diet-Induced Obesity

Luteolin Attenuates Hepatic Steatosis and Insulin Resistance Through the Interplay Between the Liver and Adipose Tissue in Mice with Diet-Induced Obesity

Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and xenobiotics

Chloroacetaldehyde as a Sulfhydryl Reagent: The Role of Critical Thiol Groups in Ifosfamide Nephropathy

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