In vivo role of NAD(P)H:quinone oxidoreductase 1 in metabolic activation of mitomycin C and bone marrow cytotoxicity.
NAD(P)H:quinone oxidoreductase 1(-/-) (NQO1(-/-)), NQO1(+/-) along with NRH:quinone oxidoreductase 2(-/-) (NQO2(-/-)), and wild-type (WT) mice were exposed to five once weekly doses of mitomycin C. The mice were euthanized 15 weeks after the first dose. Blood cell counts and histologic analyses were done. WT and NQO2(-/-) mice showed hypocellularity and a significant increase in adipocytes in bone marrow. They also showed anemia because of the loss of RBC and hemoglobin. The neutrophils and platelets were reduced, whereas other blood cell types and tissues were normal. Interestingly, NQO1(-/-) mice showed a complete resistance to mitomycin C-induced bone marrow cytotoxicity and reduction in RBC, hemoglobin, and neutrophils. NQO1(+/-) mice also showed limited resistance to mitomycin C-induced bone marrow cytotoxicity. These data show a major in vivo role of NQO1 in metabolic activation of mitomycin C with implications in mitomycin C chemotherapy.
Adikesavan
Anbu Karani
AK
Department of Pharmacology, Baylor College of Medicine and Department of Pathology, Methodist Hospital, Houston, TX, USA.
Barrios
Roberto
R
Jaiswal
Anil K
AK
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000378:metabolism; D001711:Biotransformation; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D004906:Erythrocyte Count; D005260:Female; D006454:Hemoglobins / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016685:Mitomycin / Q000009:adverse effects* / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000235:genetics / Q000502:physiology*