Critical depurinating DNA adducts: Estrogen adducts in the etiology and prevention of cancer and dopamine adducts in the etiology and prevention of Parkinson's disease

Abstract

Endogenous estrogens become carcinogens when dangerous metabolites, the catechol estrogen quinones, are formed. In particular, the catechol estrogen-3,4-quinones can react with DNA to produce an excess of specific depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating subsequent cancer-initiating mutations. Unbalanced estrogen metabolism yields excessive catechol estrogen-3,4-quinones, increasing formation of depurinating estrogen-DNA adducts and the risk of initiating cancer. Evidence for this mechanism of cancer initiation comes from various types of studies. High levels of depurinating estrogen-DNA adducts have been observed in women with breast, ovarian or thyroid cancer, as well as in men with prostate cancer or non-Hodgkin lymphoma. Observation of high levels of depurinating estrogen-DNA adducts in high risk women before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Formation of analogous depurinating dopamine-DNA adducts is hypothesized to initiate Parkinson's disease by affecting dopaminergic neurons. Two dietary supplements, N-acetylcysteine and resveratrol complement each other in reducing formation of catechol estrogen-3,4-quinones and inhibiting formation of estrogen-DNA adducts in cultured human and mouse breast epithelial cells. They also inhibit malignant transformation of these cells. In addition, formation of adducts was reduced in women who followed a Healthy Breast Protocol that includes N-acetylcysteine and resveratrol. When initiation of cancer is blocked, promotion, progression and development of the disease cannot occur. These results suggest that reducing formation of depurinating estrogen-DNA adducts can reduce the risk of developing a variety of types of human cancer.

Helminth infection-induced carcinogenesis: spectrometric insights from the liver flukes, Opisthorchis and Fasciola

“…We hypothesised that these helminths produce and release derivatives of oestrogens and oxysterols that promote oxidation of host DNA, inducing lesions, adducts and mutations [1,3–6]. The findings supported the postulate that these infection-associated cancers originate from a biological and/ or chemical insult followed by chronic inflammation, fibrosis, and a change in the tissue microenvironment that leads to a pre-cancerous niche [7,8]. Paradoxically, infections with other close phylogenetic relatives of these carcinogenic helminths, also food borne trematodes of the Phylum Platyhelminthes (Table 1), have not been categorized as group 1 biological carcinogens [9–15].…”

Oroxylin A, a methylated metabolite of baicalein, exhibits a stronger inhibitory effect than baicalein on the CYP1B1‐mediated carcinogenic estradiol metabolite formation

“…The high and consistent expressions of CYP1A1 and 1B1 have been confirmed in breast tumors (Cui et al, ). 17β‐estradiol‐3,4‐quinones generated from oxidation of 4‐OHE2 produce predominantly mutagenic depurinating adducts as well as cause DNA oxidative damage and lead to the development and evolution of breast cancer (Figure a; Cavalieri, Rogan, & Zahid, ; Do et al, ). Further studies have reported that 4‐OHE2 suppress apoptosis, promote proliferation and metastasis of human breast cancer cells (Seeger, Wallwiener, Kraemer, & Mueck, ; Gregoraszczuk & Ptak, ).…”

“…Further studies have reported that 4‐OHE2 suppress apoptosis, promote proliferation and metastasis of human breast cancer cells (Seeger, Wallwiener, Kraemer, & Mueck, ; Gregoraszczuk & Ptak, ). In contrast, 17β‐estradiol‐2,3‐semiquinones derived from 2‐OHE2 produce stable and less harmful DNA adducts (Figure a; Cavalieri et al, ). Additionally, the ratio of 4‐/2‐OHE2 formation in neoplastic mammary tissue is higher than that in normal tissue, indicating the ratio is one of the important markers of benign or malignant breast tumors (Cavalieri et al, ; Samavat & Kurzer, ).…”

“…In contrast, 17β‐estradiol‐2,3‐semiquinones derived from 2‐OHE2 produce stable and less harmful DNA adducts (Figure a; Cavalieri et al, ). Additionally, the ratio of 4‐/2‐OHE2 formation in neoplastic mammary tissue is higher than that in normal tissue, indicating the ratio is one of the important markers of benign or malignant breast tumors (Cavalieri et al, ; Samavat & Kurzer, ). Thus, it has been suggested that inhibition of CYP1B1, an important drug target, is obviously a breast cancer preventive/therapeutic strategy (Cui et al, ; Li, Zhu, & Gonzalez, ).…”

The experimental study of the pathogenic role of NADPH-oxidase in the thyroid gland tissues

“…Estrogen can also stimulate proliferation of thyroid cells, or, more likely, stem cells of the thyroid gland via the receptor-mediated pathway, or by enhancing the stimulation of thyroid gland NADPH oxidase [12][13][14][15] . This latter phenomenon is of particular importance, since it can explain not only the oncogenic ability of estrogen, but also the cause of the higher frequency of autoimmune diseases of the thyroid gland in women [16][17][18] . In addition, estrogens are involved in the regulation of angiogenesis and metastasis, which are crucial for the outcome of thyroid cancer 19-20. .…”