Reduced nicotinamide adenine dinucleotide phosphate and the higher incidence of pollution-induced liver cancer in female flounder.

In biological effect monitoring programs, induction of biotransformation and detoxification enzymes is used as a biomarker for pollution. Yet sex differences are usually neglected in the availability of reduction equivalents needed in these metabolic pathways and may affect biomarker responses. For example, female flounder have a threefold higher incidence of macroscopic liver nodules than males of the same age class in polluted environments of the North Sea that progress toward carcinomas, whereas tumors in males virtually never develop into cancer. Evidence is presented in this review that NADPH plays a significant role in this sex-related response to xenobiotics in liver of flounder. The NADPH is needed for biosynthesis, particularly of lipids and lipoproteins, and detoxification processes such as one-electron and two-electron biotransformation and conjugation and, therefore, its availability as substrate determines biomarker responses. Biotransformation of xenobiotics is more strongly induced and conjugation processes are less affected in male flounder liver during exposure. In female liver, NADPH is required for production of the yolk precursor protein vitellogenin for oocyte production. The latter process has a higher priority than the NADPH-requiring detoxification processes because reproductive success is more relevant in evolutionary perspectives than the survival of the individual female. The data reviewed here suggest that these sex-related differences in NADPH metabolism are a major cause of the higher incidence of liver cancer in female flounder in polluted environments.