Effects of spaced feeding on gene expression of hepatic transaminase and gluconeogenic enzymes in rats

Kobayashi, Akio; Yokoyama, Hisayuki; Kataoka, Jiro; Ishida, Tomio; Kuno, Hideyuki; Sugai, Shoichiro; Sakakibara, Hiroyuki; Shimoi, Kayoko

doi:10.2131/jts.36.325

Cited by 17 publications

(32 citation statements)

References 33 publications

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“…The plasma glucose levels in the control RF rats were maintained at the same levels as in the control ALF rats throughout the experiment period except for the early stage of the experimental period. This result is consistent with those previously reported (Kobayashi et al, 2011). In a state of caloric restriction, the liver produces glucose from muscle-derived alanine via the glucose-alanine cycle (Dhahbi et al, 1999;Felig, 1973;Chakrabarty and Leveille, 1968) and, in the RF rats, the plasma glucose levels were considered to be maintained mainly by hepatic gluconeogenesis using alanine supplied by the muscles after the adaptation to the restricted feeding condition (Garber et al, 1976;Leveille and Chakrabarty, 1968).…”

Section: Discussionsupporting

confidence: 92%

“…We focused on the nutritional state which is one of the risk factors of the APAP-induced hepatotoxicity in humans and investigated APAP-induced hepatotoxicity with the restricted fed rats because the daytime-RF rats are well known to show some characteristic adaptive changes in energy metabolism, glucose synthesis and fatty acid oxidation associated with a shift of the animal's circadian rhythms (Báez-Ruiz et al, 2005;Leveille and Chakrabarty, 1968;Satoh et al, 2006;Wu et al, 2008) and to show acceleration of hepatic gluconeogenesis under restricted feeding conditions (Kobayashi et al, 2011) .…”

Section: Discussionmentioning

confidence: 99%

“…Further, intact rats more easily adapt to drugs including APAP than humans (O'Brien et al, 2000;Buttar et al, 1976Buttar et al, , 1977Strubelt et al, 1979;Poulsen and Thomsen, 1988;Shayiq et al, 1999). Thus, we employed daytime restricted fed (RF) rats as a modified-nutritional state model for human responders to APAP-induced hepatotoxicity because daytime-RF rats are well known to show some characteristic adaptive changes in energy metabolism, glucose synthesis and fatty acid oxidation associated with a shift of the animal's circadian rhythms (Baez-Ruiz et al, 2005;Leveille and Chakrabarty, 1968;Satoh et al, 2006;Wu et al, 2008) and to show acceleration of hepatic gluconeogenesis under restricted feeding conditions (Kobayashi et al, 2011) . In the present study, plasma and urinary endogenous metabolites were also compared between ad libitum fed (ALF) rats and RF rats before and after repeated dosing of APAP.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…These results indicate that the higher levels of hepatic function parameters in the SDT fatty rats are not related to hepatotoxicity. Transaminases are involved in the alanine-glucose cycle and the activity of transaminase is increased in the liver or small intestine when gluconeogenesis and protein catabolism are accelerated (Hagopian et al, 2003;Kobayashi et al, 2009Kobayashi et al, , 2011. GLDH is also involved in the alanine-glucose cycle and may be increased when gluconeogenesis and protein catabolism are accelerated.…”

Section: Strainmentioning

confidence: 99%

Estimation of potential risk of allyl alcohol induced liver injury in diabetic patients using type 2 diabetes spontaneously diabetic Torii-<i>Lepr<sup>fa</sup></i> (SDT fatty) rats

et al. 2019

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In order to estimate the potential risk of chemicals including drug in patients with type 2 diabetes mellitus (T2DM), we investigated allyl alcohol induced liver injury using SD rats and Spontaneously Diabetic Torii-Lepr fa (SDT fatty) rats as a model for human T2DM. The diabetic state is one of the risk factors for chemically induced liver injury because of lower levels of glutathione for detoxification by conjugation with chemicals and environmental pollutants and their reactive metabolites. Allyl alcohol is metabolized to a highly reactive unsaturated aldehyde, acrolein, which is detoxified by conjugation with glutathione. Therefore, we used allyl alcohol as a model compound. Our investigations showed that SDT fatty rats appropriately mimic the diabetic state in humans. The profiles of glucose metabolism, hepatic function tests and glutathione synthesis in the SDT fatty rats were similar to those in patients with T2DM. Five-week oral dosing with allyl alcohol to the SDT fatty rats revealed that the allyl alcohol induced liver injury was markedly enhanced in the SDT fatty rats when compared with the SD rats and the difference was considered to be due to lower hepatic detoxification of acrolein, the reactive metabolite of allyl alcohol, by depleted hepatic glutathione synthesis. Taking all the results of the present study into consideration, the potential for allyl alcohol to induce liver injury is considered to be higher in diabetic patients than in healthy humans.

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“…These transaminase activities are also recognized to be altered by hormonal and nutritional modifications such as glucocorticoid-treatment, feeding on a high fat diet and dietary restriction (Ramesh and Pugalendi, 2006;Rosen et al, 1959;Hoffman et al, 1989;Katchman and Zipf, 1970;Kobayashi et al, 2010Kobayashi et al, , 2011. Therefore, if a drug affects the amino acid/glucose metabolism pathway by its pharmacological actions, the transaminase activities will be altered in both the tissues and blood.…”

Section: Introductionmentioning

confidence: 99%

A pharmacologic increase in activity of plasma transaminase derived from small intestine in animals receiving an acyl CoA: diacylglycerol transferase (DGAT) 1 inhibitor

Yokoyama¹,

Kobayashi²,

Kondo³

et al. 2018

J. Toxicol. Sci.

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Acyl CoA: diacylglycerol acyltransferase (DGAT) 1 is an enzyme that catalyzes the re-synthesis of triglycerides (TG) from free fatty acids and diacylglycerol. JTT-553 is a DGAT1 inhibitor and exhibits its pharmacological action (inhibition of re-synthesis of TG) in the enterocytes of the small intestine leading to suppression of a postprandial elevation of plasma lipids. After repeated oral dosing JTT-553 in rats and monkeys, plasma transaminase levels were increased but there were neither changes in other hepatic function parameters nor histopathological findings suggestive of hepatotoxicity. Based on the results of exploratory studies for investigation of the mechanism of the increase in transaminase levels, plasma transaminase levels were increased after dosing JTT-553 only when animals were fed after dosing and a main factor in the diet contributing to the increase in plasma transaminase levels was lipids. After dosing JTT-553, transaminase levels were increased in the small intestine but not in the liver, indicating that the origin of transaminase increased in the plasma was not the liver but the small intestine where JTT-553 exhibits its pharmacological action. The increase in small intestinal transaminase levels was due to increased enzyme protein synthesis and was suppressed by inhibiting fatty acid-transport to the enterocytes. In conclusion, the JTT-553-related increase in plasma transaminase levels is considered not to be due to release of the enzymes from injured cells into the circulation but to be phenomena resulting from enhancement of enzyme protein synthesis in the small intestine due to the pharmacological action of JTT-553 in this organ.

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Effects of spaced feeding on gene expression of hepatic transaminase and gluconeogenic enzymes in rats

Cited by 17 publications

References 33 publications

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

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

Estimation of potential risk of allyl alcohol induced liver injury in diabetic patients using type 2 diabetes spontaneously diabetic Torii-<i>Lepr<sup>fa</sup></i> (SDT fatty) rats

A pharmacologic increase in activity of plasma transaminase derived from small intestine in animals receiving an acyl CoA: diacylglycerol transferase (DGAT) 1 inhibitor

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