Effects of cysteine on amino acid concentrations and transsulfuration enzyme activities in rat liver with protein–calorie malnutrition

Kim, Yoon G.; Kim, Sang Kyum; Kwon, Jong Won; Park, Ock J.; Kim, Sang G.; Kim, Young C.; Lee, Myung G.

doi:10.1016/s0024-3205(02)02366-4

Cited by 32 publications

(19 citation statements)

References 33 publications

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“…These results, especially in conjunction with our previous studies demonstrating that insulin increases glutathione S-transferase expression and suppresses CYP2E1 expression (Woodcroft et al, 2002;Kim et al, 2003e), suggest that impairment of the antioxidant defense system may be a contributing factor to the increased oxidative stress and incidence of hepatic disease observed during diabetes. Moreover, this study implicates insulin-signaling pathways involving PI3K/Akt/ p70S6K in the insulin-mediated regulation of GCLC expression and GSH synthesis.…”

Section: Discussionsupporting

confidence: 82%

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Insulin Signaling Regulates γ-Glutamylcysteine Ligase Catalytic Subunit Expression in Primary Cultured Rat Hepatocytes

Kim

Woodcroft

Khodadadeh

et al. 2004

J Pharmacol Exp Ther

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Decreased glutathione (GSH) levels and ␥-glutamylcysteine ligase (GCL) activity have been observed in diabetic patients, and insulin reportedly increases GSH synthesis via increased GCL catalytic subunit (GCLC) gene expression. The signaling pathways responsible for mediating insulin effects on GCLC expression and GSH levels, however, are unknown. The signaling pathways involved in the regulation of GSH synthesis in response to insulin were examined in primary cultured rat hepatocytes. GSH levels, GCL activity, GCLC protein, and mRNA levels were increased to 140, 160, 600, and 340% of that monitored in untreated cells, respectively, in hepatocytes cultured with 100 nM insulin. The phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002 [2-(4-morpholinyl)-9-phenyl-4H-1-benzopyran-4-one], dominant-negative Akt, or rapamycin, an inhibitor of mTOR (mammalian target of rapamycin) and ribosomal p70 S6 kinase (p70S6K) phosphorylation, inhibited the insulin-mediated increase in GCLC protein and GSH levels. Although the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase, p38 MAPK, and JNK (c-Jun N-terminal kinase) were activated in response to insulin, PD98059 (2Ј-amino-3Ј-methoxyflavone), an inhibitor of mitogen-activated protein kinase kinase, SP600125 (1,9-pyrazoloanthrone), an inhibitor of JNK, and SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole], an inhibitor of p38 MAPK, failed to inhibit the insulin-mediated increase in GCLC protein levels. In conclusion, these data show that insulin signaling pathways involving PI3K/Akt/p70S6K, but not MAPKs, are active in the insulin-mediated regulation of GSH synthesis via increased GCLC expression.Reduced glutathione (GSH) serves several vital intracellular functions, including detoxifying electrophiles, scavenging free radicals, maintaining the essential thiol status of proteins, and providing a reservoir for cysteine (Meister and Anderson, 1983;DeLeve and Kaplowitz, 1991;Lu, 1999). Thus, maintenance of GSH levels is pivotal for cellular defense against oxidative injury and for cellular integrity. Although several organs can take up GSH directly from blood, most organs, including liver, depend on de novo GSH synthesis to maintain their intracellular GSH content (Ookhtens and Kaplowitz, 1998). The synthesis of GSH from its constituent amino acids involves two ATP-requiring enzymatic steps: the formation of ␥-glutamylcysteine from glutamate and cysteine and formation of GSH from ␥-glutamylcysteine and glycine. The first step of GSH biosynthesis is rate-limiting and catalyzed by ␥-glutamylcysteine ligase (GCL). GCL consists of a regulatory or light subunit (GCLR) and a catalytic or heavy subunit (GCLC). Because GCL is a major determinant of GSH synthesis capacity, regulation of GCL subunits has been a topic of extensive research.Oxidative stress is increased in diabetic conditions (West, 2000) and is a major factor contributing to chronic complications of diabetes (Baynes and Thorpe, 1999). O...

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Section: Discussionsupporting

confidence: 82%

“…Thirty minutes after 10 nM insulin treatment, whole cell lysates were prepared as described previously (Kim et al, 2003e). Akt immunoprecipitation and kinase assay were carried out following the procedures in the kit as described by the manufacture (Cell Signaling Technology).…”

Section: Methodsmentioning

confidence: 99%

Insulin Signaling Regulates γ-Glutamylcysteine Ligase Catalytic Subunit Expression in Primary Cultured Rat Hepatocytes

Kim

Woodcroft

Khodadadeh

et al. 2004

J Pharmacol Exp Ther

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“…The change in the cellular redox state in conjunction with oxidative stress has been reported to result in the transcriptional activation of some GST genes (Wasserman and Fahl, 1997;Kang et al, 2001a). Glutathione (GSH) synthesis can also be altered in response to pathophysiologic conditions such as diabetes, protein-calorie malnutrition and alcohol consumption through regulation of gamma-glutamylcysteine ligase (GCL) expression, the enzyme which catalyzes the first step of GSH synthesis, and by the availability of cysteine for GSH synthesis (Yoshida et al, 1995;Lu et al, 1999;Kim et al, 2003c).…”

Section: Generalmentioning

confidence: 99%

The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

Kim

Novak

2007

Pharmacology & Therapeutics

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142

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Endogenous factors, including hormones, growth factors and cytokines, play an important role in the regulation of hepatic drug metabolizing enzyme expression in both physiological and pathophysiological conditions. Alterations of hepatic drug metabolizing enzymes gene and protein expression, observed in diabetes, fasting, obesity, protein-calorie malnutrition and long-term alcohol consumption alters the metabolism of xenobiotics, including procarcinogens, carcinogens, toxicants, and therapeutic agents and may also impact the efficacy and safety of therapeutic agents, as well as result in drug-drug interactions. Although the mechanisms by which xenobiotics regulate drug metabolizing enzymes have been studied intensively, less is known regarding the cellular signaling pathways and components which regulate drug metabolizing enzyme gene and protein expression in response to hormones and cytokines. Recent findings, however, have revealed that several cellular signaling pathways are involved in hormone-and growth factor-mediated regulation of drug metabolizing enzymes. Our laboratory, and others, have demonstrated that insulin and growth factors regulate drug metabolizing enzyme gene and protein expression, including cytochromes P450, glutathione S-transferases and microsomal epoxide hydrolase, through receptors which are members of the large receptor tyrosine kinase family, and by downstream effectors such as phosphatidylinositol 3-kinase, the mitogen activated protein kinase, Akt/protein kinase B, mTOR, and the p70S6 kinase. Here, we review current knowledge of the signaling pathways implicated in regulation of drug metabolizing enzyme gene and protein expression in response to insulin and growth factors, with the goal of increasing our understanding of how chronic disease affects these signaling pathways, components, and ultimately gene expression and translational control.

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“…The existance of sulfur-containing-amino acid within cysteine residue acted as stronger antioxidants, produce H2O2 in the presence of transition metal ions (Atmaca, 2004;Flora, 2009). Furthermore, this thiol antioxidant is able to protect the death of the cells by their proglutathione properties, rather than reactive oxygen direct scavenging (Kim et al, 2003;Sen et al, 1997). Based on QSAR method, cysteine was predicted as the most active antioxidant amino acid, especially in tripeptides structure (Tian et al, 2015).…”

Section: Antioxidant Activity Of Purified Peptidementioning

confidence: 99%

Antioxidant Activity of Purified Active Peptide Derived from Spirulina platensis Enzymatic Hydrolysates

Safitri

Herawati

Hsu

2017

RJLS

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The aim of this study is to isolate the antioxidative peptide from Spirulina platensis. Peptide was obtained by proteolytic digestion, ultrafiltration, fractionation by RP-HPLC, identified by LC-MS/MS-MASCOT Distiller and measured its antioxidant activity by DPPH (2.2-Diphenyl-1-picrylhydrazyl) assay. Results showed that thermolysin was the most effective enzyme to digest this algae. The active peptide PheSer-Glu-Ser-Ser-Ala-Pro-Glu-Gln-His-Tyr (m/z 1281.51) was identified and synthetized, which exhibited 45.98 ± 1.7% at concentration 128.15 µg/mL. Therefore, S. platensis is indicated as a potential therapeutic source for combating oxidative stress.

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Effects of cysteine on amino acid concentrations and transsulfuration enzyme activities in rat liver with protein–calorie malnutrition

Cited by 32 publications

References 33 publications

Insulin Signaling Regulates γ-Glutamylcysteine Ligase Catalytic Subunit Expression in Primary Cultured Rat Hepatocytes

Insulin Signaling Regulates γ-Glutamylcysteine Ligase Catalytic Subunit Expression in Primary Cultured Rat Hepatocytes

The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

Antioxidant Activity of Purified Active Peptide Derived from Spirulina platensis Enzymatic Hydrolysates

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