Estrogen Metabolites in the Etiology of Hormone Related Cancers: Possible Role of Anti-Oxidants in Prevention

The goal of this review is to demonstrate the role of metabolic variations in estrogen metabolism and polymorphisms in enzymatic control in the oncogenesis of breast and prostate cancer and Parkinsonism. Further biochemical associations with these cancers are demonstrated. The evidence for interference of oncogenic metabolites by certain anti-oxidants is reviewed. The role of endogenous hormones particularly estrogens in the etiology of several cancers has been postulated for several decades. Benzene has long been associated with leukemia. The benzene ring which includes estrogens, benzene and dopamine are metabolized to orthoquinones which are highly electrophilic and have been shown to be depurinating to DNA. These metabolites are known as estrogen adducts (EA). Estrogen is metabolized in steps involving formation of hydroxyl-estrogens further oxidized by CYP 450 enzymes or peroxidases or by catechol o methyl transferase, and finally by glutathione. In vivo studies demonstrate induction of altered DNA due to purine base knockouts leading to malignant transformation in MC-10 mouse cell lines. Further evidence reveals these changes are not estrogen receptor dependent. Statistically higher urinary levels of EAs have been demonstrated in women with a history of breast cancer and that of men with prostate cancer and lymphoma, as well as in malignant human breast epithelial tissue. In a genetic population of high risk cancers, manifested by BRCA 1 and 2 alterations, DNA double stranded breaks are increased when mice cells are incubated with EAs. BRCA mutations are responsible for induction of substrate metabolites 2-OH E2 and 4 OH E2 by failure of control of cytochrome P450 enzymes (aromatizes) as well as inhibition of quinone oxoreductase which reduces estrogen quinones to lessen formation of EAs. Adducts have an important role in neurotransmitter metabolism, for example in the formation of dopamine quinone DNA adducts. Loss of dopamine in the substantia nigra and metabolic changes in dopamine metabolism may have a role in the pathophysiology of Parkinson’s disease. At lower pH ranges dopamine (DA) quinone is metabolized to lead to increasing competitive increase in electrophilic attraction to nucleotide adducts DA-6-N3 Ade and DA 6-N7 Gua which lead to mutagenesis and degeneration in cells of the subsantia nigra. Further research has demonstrated that antioxidants, resveratrol and N-acetyl cysteine (NAc) inhibit formation of EAs in cultured mammary tissue of MC-10 mice, by enhancement of quinone reductase and inhibition of attachment of quinones to DNA purines through glutathione induction. In the case of DA metabolism, reduction of quinone nucleotide activity was demonstrated with the use of lipoic acid, NAc, melatonin and resveratrol. Further clinical trials and epidemiologic studies in humans with described cancers and Parkinson disease are necessary to define these models and prevention in the future.