Modulation of intracellular glutathione concentration alters dehydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells.
Dehydropyrimidine dehydrogenase (DPD) is the initial key enzyme in the regulation of 5-fluorouracil catabolism and thus controls availability of 5-fluorouracil for anabolism. Modulation of DPD activity may increase the antitumor effect and avoid toxic side effects in 5-fluo-rouracil-based chemotherapy. We measured DPD activity in peripheral blood mononuclear cells from cancer patients and simultaneously monitored intracellular glutathione (GSH) and plasma GSH levels. There was a significant linear relationship between DPD activity and intracellular GSH levels in peripheral blood mononuclear cells obtained from cancer patients. Suppression of intracellular GSH level by buthionine sulfoximine decreased DPD activity, while enhancement of intracellular GSH level by 2-mercaptoethanol increased DPD activity. This study indicated that alteration of intracellular GSH concentration may modulate DPD activity.
Department of Gastroenterological Surgery and Oncology, Kitano Hospital, The Tazuke Kohukai Medical Research Institute, Osaka, Japan. iwata@hosp.city.kyoto.jp
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Iwata
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Takabayashi
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Yamaoka
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D002470:Cell Survival; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000494:pharmacology; D005978:Glutathione / Q000097:blood*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000097:blood*; D013274:Stomach Neoplasms / Q000097:blood / Q000201:enzymology
D000964:Antimetabolites, Antineoplastic; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005978:Glutathione; D005472:Fluorouracil