NAD(P)H：醌氧化还原酶1在丝裂霉素C代谢活化及骨髓细胞毒性中的体内作用

In vivo role of NAD(P)H:quinone oxidoreductase 1 in metabolic activation of mitomycin C and bone marrow cytotoxicity.

作者信息

Adikesavan Anbu Karani, Barrios Roberto, Jaiswal Anil K

机构信息

Department of Pharmacology, Baylor College of Medicine and Department of Pathology, Methodist Hospital, Houston, TX, USA.

出版信息

Cancer Res. 2007 Sep 1;67(17):7966-71. doi: 10.1158/0008-5472.CAN-06-4480.

DOI:10.1158/0008-5472.CAN-06-4480

PMID:17804703

Abstract

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.

摘要

将烟酰胺腺嘌呤二核苷酸磷酸（NAD(P)H）：醌氧化还原酶1（-/-）（NQO1（-/-））、NQO1（+/-）与烟酰胺腺嘌呤二核苷酸（NRH）：醌氧化还原酶2（-/-）（NQO2（-/-））以及野生型（WT）小鼠，每周一次给予5剂丝裂霉素C。在首次给药后15周对小鼠实施安乐死。进行血细胞计数和组织学分析。野生型和NQO2（-/-）小鼠骨髓显示细胞减少且脂肪细胞显著增加。它们还因红细胞和血红蛋白减少而出现贫血。中性粒细胞和血小板减少，而其他血细胞类型和组织正常。有趣的是，NQO1（-/-）小鼠对丝裂霉素C诱导的骨髓细胞毒性以及红细胞、血红蛋白和中性粒细胞减少表现出完全抗性。NQO1（+/-）小鼠对丝裂霉素C诱导的骨髓细胞毒性也表现出有限抗性。这些数据表明NQO1在丝裂霉素C的代谢活化中具有主要的体内作用，这对丝裂霉素C化疗具有重要意义。