DIFFERENTIAL TOXICITY OF MITOMYCIN-C AND PORFIROMYCIN TO AEROBIC AND HYPOXIC CHINESE-HAMSTER OVARY CELLS OVEREXPRESSING HUMAN NADPH-CYTOCHROME-C (P-450) REDUCTASE
Mf. Belcourt et al., DIFFERENTIAL TOXICITY OF MITOMYCIN-C AND PORFIROMYCIN TO AEROBIC AND HYPOXIC CHINESE-HAMSTER OVARY CELLS OVEREXPRESSING HUMAN NADPH-CYTOCHROME-C (P-450) REDUCTASE, Proceedings of the National Academy of Sciences of the United Statesof America, 93(1), 1996, pp. 456-460
Purified NADPH:cytochrome c (P-450) reductase (FpT; NADPH-ferrihemopro
tein oxidoreductase, EC 1.6.2.4) can reductively activate mitomycin an
tibiotics through a one-electron reduction to species that alkylate DN
A, To assess the involvement of FpT in the intracellular activation of
the mitomycins, transfectants overexpressing a human FpT cDNA were es
tablished from a Chinese hamster ovary cell line deficient in dihydrof
olate reductase (CHO-K1/dhfr(-)). The parental cell line was equisensi
tive to the cytotoxic action of mitomycin C under oxygenated and hypox
ic conditions, In contrast, porfiromycin cin was considerably less cyt
otoxic to wild-type parental cells than was mitomycin C in air and mar
kedly more cytotoxic under hypoxia. Two FpT-transfected clones were se
lected that expressed 19- and 27-fold more FpT activity than the paren
tal line, Levels of other oxidoreductases implicated in the activation
of the mitomycins were unchanged, Significant increases in sensitivit
y to mitomycin C and porfiromycin in the two FpT-transfected clones we
re seen under both oxygenated and hypoxic conditions, with the increas
es in toxicity being greater under hypoxia than in air, These findings
demonstrate that FpT can bioreductively activate the mitomycins in li
ving cells and implicate FpT in the differential aerobic/hypoxic toxic
ity of the mitomycins.