Glutathione depletion by 2-nitroimidazole-1-acetohydroxamic acid as a radiosensitizer in hypoxic rat hepatocytes.
The effects of nitroimidazoles as radiosensitizers on intracellular glutathione (GSH) level were investigated in rat isolated hepatocytes. Dinitroimidazoles have lowered almost completely GSH level during the incubation for 30 min under oxic (95% O2+5% CO2) condition, while mononitroimidazoles had scarcely affected. In the case of hypoxic (95% N2+5% CO2) condition, however, 2-nitroimidazoles, not 4-nitroimidazoles, as well as 2,4- and 4,5-dinitroimidazoles have caused the significant depletion of GSH. This suggests that nitro group in the 2-position of imidazoles may be responsible for the GSH depletion under hypoxia. Especially, 2-nitroimidazole-1-acetohydroxamic acid (KIH-801) was found to be the most potent GSH depletor only under hypoxic, not oxic conditions, and might be useful for the new hypoxic cell radiosensitizer instead of misonidazole.
Takanuki
K
K
Department of Biochemical Pharmacology and Biotoxicology, Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Igarashi
T
T
Hata
K
K
Hori
H
H
Shibata
T
T
Kitagawa
H
H
Satoh
T
T
Inayama
S
S
D000818:Animals; D005978:Glutathione / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009593:Nitroimidazoles / Q000494:pharmacology*; D010100:Oxygen / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C057685:2-nitroimidazole-1-acetohydroxamic acid; D005978:Glutathione; D010100:Oxygen