Abstract
NAD(P)H:quinone oxidoreductase 1 (NQO1; DT-diaphorase; DTD) is a cytosolic two-electron reductase, and compounds of the family of quinones such as mitomycin C are efficiently bio-activated by this enzyme. The observation that DT-diaphorase is over-expressed in many cancerous tissues compared to normal tissues has provided us with a selective target that can be exploited in the design of novel anticancer agents. Because information about the cell-specific expression of DT-diaphorase was so scarce, this study was initiated to map the distribution of this enzyme in human tissues. We report here our findings concerning the reproductive organs. Tissue samples taken from various components of the human reproductive system were analysed for expression of DT-diaphorase by immunohistochemistry. We found a strong expression of this enzyme in testicular stromal cells (Leydig’s cells) and in the epithelium of the epididymis and Fallopian tube. These results suggest that quinones bio-activated by DT-diaphorase may be toxic to the reproductive system and cause clinical problems due to testosterone deficiency in men and infertility in both sexes. The implications of these observations need to be considered in pre-clinical evaluation of new anticancer quinones and in patients treated with these compounds.
Highlights
Alkylating agents have been used in cancer chemotherapy for over 50 years [1] and are still among the most widely administered and effective anti-tumour drugs
These results suggest that quinones bio-activated by DT-diaphorase may be toxic to the reproductive system and cause clinical problems due to testosterone deficiency in men and infertility in both sexes
The specificity of agents of this type against tumour cells depends on the activity of the bio-reductive enzyme DT-diaphorase (NQO1; NAD(P)H:quinone oxidoreductase 1; DTD)
Summary
Alkylating agents have been used in cancer chemotherapy for over 50 years [1] and are still among the most widely administered and effective anti-tumour drugs They are reactive chemicals that form covalent bonds with a variety of chemical groups on essential cellular molecules, but their reaction with DNA appears to be the primary event that causes cell death. DT-diaphorase over-expression has been demonstrated in many cancerous tissues compared to normal tissues [7,8] This allows the generation of higher concentrations of reactive compounds at the tumour site by the utilisation of DTD-activated pro-drugs. DT-diaphorase is believed to protect normal cells against redox cycling and oxidative stress by the reductive detoxification of quinones and their derivatives Quinones such as mitomycin C and streptonigrin have been used for 40 years and are active against head and neck, breast, gastrointestinal and lung cancers. We report our findings concerning the analysis of DTD expression in different components of the human reproductive system
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