Naphthazarin derivatives (V): formation of glutathione conjugate and cytotoxic activity of 2-or 6-substituted 5,8-dimethoxy-1,4-napthoquinones in the presence of glutathione-S-transferase, in rat liver S-9 fraction and mouse liver perfusate.
Formation of glutathione (GSH) conjugates with 2- or 6-(1-hydroxymethyl)- and 2-(1-hydroxyethyl)-DMNQ derivatives (DMNQ, 5,8-dimethoxy-1,4-naphthoquone) was carried out in phosphate buffer (pH 7.4), in the presence of glutathione-S-transferase (GST), in rat liver S-9 fraction and by perfusion, and the rates of conjugates formation were compared and correlated to cytotoxicity. The GSH conjugates of 6-(1-hydroxyalkyl)-DMNQ derivatives were formed faster than 2-(1-hydroxyalkyl)-DMNQ derivatives under all of the media, implying that steric hindrance was the cause of lowering the rate of conjugate formation of 2-substituted derivatives. For both isomers, addition of GST did not improve the reaction rate, compared with that in buffer, while the reaction in the S-9 fraction and the perfusate was accelerated to a great extent. The catalytic effect of the S-9 fraction and the perfusion on 2-isomers was greater than on 6-substituted ones, suggesting that S-9 fraction and the perfusate contain an effective system relaxing the steric hindrance of 2-(1-hydroxyalkyl)-DMNQ derivatives. Furthermore, a good correlation between the formation of the GSH conjugates and the cytotoxic activity of both naphthazarin isomers suggests that the steric hindrance is a cause of lowering the cytotoxicity of 2-isomers.
Zheng
X G
XG
College of Pharmacy, Chungnam National University, Taejon, Korea.
Kang
J S
JS
Kim
H M
HM
Jin
G Z
GZ
Ahn
B Z
BZ
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D009285:Naphthoquinones / Q000378:metabolism* / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009285:Naphthoquinones; C005503:naphthazarin; D005982:Glutathione Transferase; D005978:Glutathione