Knock Down of γ-Glutamylcysteine Synthetase in Rat Causes Acetaminophen-induced Hepatotoxicity

Akai, Shigeyasu; Hosomi, Hiroko; Minami, Kenji; Tsuneyama, Koichi; Katoh, Miki; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1074/jbc.m702819200

Cited by 38 publications

(20 citation statements)

References 42 publications

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“…Meanwhile, several studies have reported on the regulation of numerous stimuli on its activity (Soltaninassab et al, 2000;Wild and Mulcahy, 2000;Franklin et al, 2009). GCL is reported to play important roles in regulating AP-induced liver injury, and the enzymatic activity and protein expression of GCL are both decreased after AP administration (Akai et al, 2007;Shinohara et al, 2010). Our results showed that FL prevented AP-induced decrease in GCL enzymatic activity, which may be due to the increased expression of the GCLC protein.…”

Section: Discussionmentioning

confidence: 40%

Protection of Flos Lonicerae against acetaminophen-induced liver injury and its mechanism

Jiang¹,

Sheng

Chen³

et al. 2014

Environmental Toxicology and Pharmacology

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Section: Discussionmentioning

confidence: 40%

Protection of Flos Lonicerae against acetaminophen-induced liver injury and its mechanism

Jiang¹,

Sheng

Chen³

et al. 2014

Environmental Toxicology and Pharmacology

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“…Rodents are less sensitive to APAP-induced acute hepatotoxicity than humans and this species difference is accounted for by differences in glutathione content, glutathione synthesis activity or conjugation activity of glutathione with drug metabolites in the liver between rodents and humans (Grover and Sims, 1964). This is evidenced by nonclinical studies using glutathione depletion rodent models that are more sensitive to APAP-induced acute hepatotoxicity than intact rodents (Akai et al, 2007).…”

Section: Introductionmentioning

confidence: 76%

Enhancement of acetaminophen-induced chronic hepatotoxicity in restricted fed rats: a nonclinical approach to acetaminophen-induced chronic hepatotoxicity in susceptible patients

et al. 2012

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Drug-induced Liver Injury (DILI) is becoming a significant public health issue because of its potential impact, not only on patients but also on the development of new drugs. DILI events are also the main cause of regulatory action pertaining to drugs, including denial of marketing approval, restrictions with respect to clinical indications and withdrawal from the marketplace (Lee, 2003;Smith and Schmid, 2006). Acetaminophen (APAP) is a commonly used and effective analgesic and antipyretic agent for relief of mild and moderate pain and is available as an over-the-counter medication. Overdoses of APAP, however, cause severe acute hepatotoxicity both in animals (Lauterburg et al., 1983) and humans (Black, 1984;Davidson and Eastham, 1966;Thomson and Prescott, 1966;Schiødt et al., 1997). APAP at therapeutic doses is rapidly metabolized in the liver principally through glucuronidation and sulfation, and only a small portion is oxidized by cytochrome P-450 2E1 to generate a highly reactive and cytotoxic intermediate, N-acetyl-p-benzoquinoneimine (NAPQI), which is quickly conjugated by hepatic glutathione to yield a harmless water-soluble product, mercapturic acid (Lee et ABSTRACT -Acetaminophen (APAP) is a commonly used and effective analgesic and antipyretic agent. However, some patients encounter hepatotoxicity after repeated APAP dosing at therapeutic doses. In the present study, we focused on the nutritional state as one of the risk factors of APAP-induced chronic hepatotoxicity in humans and investigated the contribution of undernourishment to susceptibility to APAP-induced chronic hepatotoxicity using an animal model mimicking undernourished patients. Rats were divided into 2 groups: the ad libitum fed (ALF) and the restricted fed (RF) rats and were assigned to 3 groups (n = 8/group) for each feeding condition. The animals were given APAP at 0, 300 and 500 mg/kg for 99 days under each feeding condition. Plasma and urinary glutathione-related metabolites and liver function parameters were measured during the dosing period and hepatic glutathione levels were measured at the end of the dosing period. In the APAP-treated ALF rats hepatic glutathione levels were increased and hepatic function parameters were not changed, but in the APAP-treated RF rats hepatic glutathione levels were decreased at 500 mg/kg and hepatic function parameters were increased at 300 and 500 mg/kg. Moreover the urinary endogenous metabolite profile after long-term treatment with APAP in the ALF and RF rats was similar to that in human non-responders and responders to APAP-induced chronic hepatotoxicity, respectively. In conclusion, the RF rats were more sensitive to APAP-induced chronic hepatotoxicity than the ALF rats and were considered to be a useful model to estimate the contribution of the nutritional state of patients to APAP-induced chronic hepatotoxicity.

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“…In experimental studies, the depletion of GSH is commonly induced by direct inhibition of GSH synthesis enzymes or in knockout models (Akai et al 2007; Wu and Cederbaum 2004). However, in general populations living in chemical-contaminated societies, a more common mechanism for GSH depletion may be GSH consumption through conjugation with chemicals or their metabolites.…”

Section: Dna Hypomethylation Through a Unifying Mechanismmentioning

confidence: 99%

Hypothesis: a Unifying Mechanism for Nutrition and Chemicals as Lifelong Modulators of DNA Hypomethylation

Lee

Jacobs

Porta

2009

Environ Health Perspect

129

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BackgroundAlthough both nutrition and chemicals are important environmental factors modulating epigenetic changes, they are commonly studied separately by researchers in different fields. However, these two environmental factors cannot be separated from each other in the real world because a number of chemical agents contaminate food chains.ObjectiveWe propose a unifying mechanism that can link epigenetic alterations in relation to DNA hypomethylation due to chemical agents and to nutrient deficiency or imbalance, emphasizing the importance of an integrative approach in the field of environmental epidemiology.DiscussionMethyl groups from S-adenosylmethionine (SAM) are needed for DNA methylation. Diets low in sources of methyl groups can lead to global DNA hypomethylation by impairing synthesis of SAM. However, even without nutritional deficiency, enhanced need to synthesize glutathi-one (GSH) can impair synthesis of SAM and perturb DNA methylation, because the methylation cycle and the GSH synthesis pathways are biochemically linked. Exposure to environmental chemicals is a common situation in which the need for GSH synthesis is enhanced, because GSH is consumed to conjugate diverse chemicals. Given that GSH conjugation happens at any chemical dose, this hypothesis is relevant even at exposures below the high doses that cause toxicologic responses.ConclusionAt present, general populations are exposed to a large number of chemicals, each at a very low dose. Thus, DNA hypomethylation due to chemical exposure may be common in modern societies and can synergistically interact with nutrition-induced DNA hypomethylation.

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Knock Down of γ-Glutamylcysteine Synthetase in Rat Causes Acetaminophen-induced Hepatotoxicity

Cited by 38 publications

References 42 publications

Protection of Flos Lonicerae against acetaminophen-induced liver injury and its mechanism

Protection of Flos Lonicerae against acetaminophen-induced liver injury and its mechanism

Enhancement of acetaminophen-induced chronic hepatotoxicity in restricted fed rats: a nonclinical approach to acetaminophen-induced chronic hepatotoxicity in susceptible patients

Hypothesis: a Unifying Mechanism for Nutrition and Chemicals as Lifelong Modulators of DNA Hypomethylation

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