Jpn. J. Pharmacol. 72 (2), 175-181 (1996)

Acetaminophen-Derived Activation of Liver Microsomal Glutathione S-Transferase of Rats

Masato Yonamine (1), Yoko Aniya (1,*), Takahiro Yokomakura (1), Tomoyuki Koyama (1), Tatsumi Nagamine (2) and Hisaharu Nakanishi (3)

(1) Laboratory of Physiology and Pharmacology, School of Health Sciences, (2) Clinical Laboratory of the University Hospital, Faculty of Medicine, University of the Ryukyus, Okinawa 903-01, Japan (3) Tropical Technology Center Limited, Okinawa 904-22, Japan (*) To whom correspondence should be addressed.

Abstract: Effect of acetaminophen on glutathione (GSH) S-transferase and related drug metabolizing enzymes was studied in vivo. Rats were given acetaminophen (250 mg/kg, i.p.) 24 hr after the treatment with 3-methylcholanthrene (25 mg/kg, i.p.) and killed by decapitation at indicated times. Liver microsomal GSH S-transferase activity was increased to 331%, 193% and 158% of the control level at 3, 6 and 12 hr, respectively, after the administration of acetaminophen, while GSH content in the liver was markedly decreased at 3 and 6 hr. The increase in the transferase activity was not recovered by the treatment with dithiothreitol. Microsomal GSH peroxidase activity was significantly enhanced at 3 hr. Cytosolic GSH S- transferase and aniline hydroxylase in microsomes were gradually decreased with the increase in the time after administration of acetaminophen. Vmax values of both GSH S-transferase and GSH peroxidase activities in microsomes were increased at 3 hr. Two Km values were obtained for the peroxidase in the control, while only one was observed after the acetaminophen treatment. These results indicate that acetaminophen is converted via cytochrome P-450 to the reactive intermediate N-acetyl-p-benzoquinone imine, which binds to microsomal GSH S-transferase, resulting in the activation of the enzyme.

Keywords: Acetaminophen, Microsome, Glutathione S-transferase, Glutathione peroxidase, Enzyme activation

Copyright© The Japanese Pharmacological Society 1996

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