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-In order to verify the nutritional aspect of alterations of the plasma and tissue transaminase activities, rats were fed 4 hr per day for 35 days (the spaced-fed (SF) rats) and the time course of the alterations in plasma and tissue transaminase activity was compared with those in the ad libitum fed (ALF) rats. Plasma transaminase activities were stable throughout the experiment period in the ALF rats. In the SF rats there were alterations in the plasma alanine aminotransferase (ALT) activities, the direction of which was different between the early phase and late phase of the experiment period; plasma ALT activities decreased in the early phase and gradually increased in the late phase. Plasma aspartate aminotransferase (AST) activities were stable in the SF rats throughout the experiment period as well as the ALF rats. The decreases in plasma ALT activities in the early phase were considered to be related to decreases in ALT activities in the small intestinal mucosa (SI mucosa). On the other hand, the increases in plasma ALT activities in the late phase were considered to be related to increases in ALT activities in the liver. Multiple regression analyses (MRAs) revealed that plasma ALT activities in the SF rats could be estimated by the ALT activities in the SI mucosa and liver. From these results, the alterations of the plasma ALT activities in the SF rats could be explained by those in the SI mucosa and liver under the conditions in our study.Key words: Alanine aminotransferase, Small intestine, Liver, Spaced feeding, RatsCorrespondence: Akio Kobayashi (E-mail: akio.kobayashi@jt.com) Original ArticleThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.35, No.5, 639-652, 2010 Vol. 35 No. 5 639 SMs as well as for other enzymes involved in the amino acid/glucose metabolism pathways if hormonal or nutritional fluctuation leading to acceleration or deceleration of gluconeogenesis and alanine synthesis, occurs. In fact, hepatic transaminase activities are increased by glucocorticoids which accelerate gluconeogenesis (Rosen et al., 1959) and/or by fluctuation in lipid metabolism including peroxisome proliferator-activated receptor alpha (PPARα) activation which is closely linked to amino acid/glucose metabolism (Kobayashi et al., 2009). In addition, hepatic ALT activities are increased in diabetic rats as the results of deficiency of insulin (Katsunuma et al., 1966). Alterations of tissue transaminase activities due to hormonal or nutritional fluctuation are also considered to result in alterations in serum or plasma transaminase activities, because serum transaminase activities reflect the activities of tissue-derived transaminases released into the circulation during normal cell turnover Schmidt, E., 1985, 1989).In the present study, we investigated the relationships between the plasma and tissue transaminase activities in rats maintained under different feeding conditions to verify the nutritional aspects of the alterations of plasma and tissue transaminase activities. As SF animals inclu...

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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