Original Paper

Effects of a Novel Hepatoprotective Drug, ZNC-2381, on Fas-Induced Hepatocellular Caspase-3 Activity and Apoptosis in Mice
Yoshihide Segawa^a, Naoki Tsuzuike^a, Yoshihiko Itokazu^a, Takeshi Omata^a, Naonori Inoue^a, Masaaki Nagasawa^a, Hiroyasu Nishioka^a, Yoshihisa Nakano^b, Tadashi Kobayashi^b, Takashi Kanda<sup>b

a</sup>Central Research Laboratories, Zeria Pharmaceutical Co., Kohnan-machi, Ohsato-gun, Saitama, and
^bResearch Laboratories, Nippon Chemiphar Co., Misato, Saitama, Japan

Address of Corresponding Author

Pharmacology 2001;62:80-86 (DOI: 10.1159/000056075)

  Key Words

• Caspase-3 activity
• Apoptosis
• Hepatocytes
• Anti-Fas antibody
• Oral drug

  Abstract

We examined the effects of ZNC-2381 (1-(4-aminophenyl)methyl-3-(3-nitrophenyl)-1,3-dihydroimidazo[4,5-b] pyridine-2-one), a new oral hepatoprotective agent, on hepatocellular caspase-3 activity and apoptosis induced by anti-mouse Fas antibody (anti-Fas ab) in mice. Oral ZNC-2381, administered at doses of 10, 30 and 100 mg/kg 1 h before inducing hepatic injury with anti-Fas ab, dose-dependently inhibited the increase in serum alanine aminotransferase (s-ALT) activity 8 h after injection of anti-Fas ab. Increases in DNA fragmentation (nucleosome assay) and caspase-3 activity in the liver 2 h after injection of anti-Fas ab were also inhibited by ZNC-2381 in a dose-dependent manner. As shown by histopathological examination, ZNC-2381 dose-dependently inhibited the appearance of TUNEL-positive apoptotic cells in the liver. Moreover, in studies in vitro, ZNC-2381 (1- 100 µmol/l) concentration-dependently inhibited increases in DNA fragmentation and caspase-3 activity caused by anti-Fas ab in isolated mouse hepatocytes. N- Acetyl-Asp-Glu-Val-Asp aldehyde (Ac-DEVD-cho), a caspase-3-specific inhibitor, inhibited hepatocellular apoptosis caused by anti-Fas ab both in vivo and in vitro, as well as the increase in s-ALT activity in vivo. These results demonstrate that orally administered ZNC-2381 inhibits hepatocellular apoptosis induced by anti-Fas ab and presents the progression of hepatic injury. We propose that the mechanism of action of ZNC-2381 may involve blockade of the signal transduction pathway (caspase-3) of apoptosis mediated by anti-Fas ab.

Copyright © 2001 S. Karger AG, Basel

  Author Contacts

Yoshihide Segawa, PhD
Central Research Laboratories, Zeria Pharmaceutical Co.
2512-1 Oshikiri, Kohnan-machi
Ohsato-gun, Saitama 360-0111 (Japan)
Tel. +81 48 536 3456, Fax +81 48 539 1072

  Article Information

Received: Received: October 25, 1999
Accepted: January 8, 2000
Number of Print Pages : 7
Number of Figures : 4, Number of Tables : 3, Number of References : 25