Co-carcinogenic effects of vitamin E in prostate

Abstract

A large number of basic researches and observational studies suggested the cancer preventive activity of vitamin E, but large-scale human intervention trials have yielded disappointing results and actually showed a higher incidence of prostate cancer although the mechanisms underlying the increased risk remain largely unknown. Here we show through in vitro and in vivo studies that vitamin E produces a marked inductive effect on carcinogen-bioactivating enzymes and a pro-oxidant status promoting both DNA damage and cell transformation frequency. First, we found that vitamin E in the human prostate epithelial RWPE-1 cell line has the remarkable ability to upregulate the expression of various phase-I activating cytochrome P450 (CYP) enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), giving rise to supraphysiological levels of reactive oxygen species. Furthermore, our rat model confirmed that vitamin E in the prostate has a powerful booster effect on CYP enzymes associated with the generation of oxidative stress, thereby favoring lipid-derived electrophile spread that covalently modifies proteins. We show that vitamin E not only causes DNA damage but also promotes cell transformation frequency induced by the PAH-prototype benzo[a]pyrene. Our findings might explain why dietary supplementation with vitamin E increases the prostate cancer risk among healthy men. Prostate cancer is the most common human malignancy and the second leading cause of cancer death among men in western nations. The high global incidence of prostate cancer, the unsatisfactory outcomes of surgery and radiotherapy and the cost of curative therapies have led to a focus on primary prevention as a major public health goal 1,2. Supported by preclinical and epidemiological evidence, antioxidants from food and supplements are widely used to protect against cancer, but clinical trials do not sustain this concept 1,3-6 and actually showed a higher incidence of prostate cancer 7,8. Conceived to break through this issue, in 2001 the National Cancer Institute (NCI) launched SELECT (Selenium and vitamin E Cancer Prevention Trial), that showed a 17% increase in prostate cancer incidence in the vitamin E arm compared to placebo 7. A growth-promoting effect of vitamin E on organoids has recently been reported 9 , but its mechanism of action remains poorly understood. Since some cytochrome P-450 (CYP) isoforms have been found overexpressed in prostate cancer 10-15 , we suspected that vitamin E could have co-carcinogenic properties such as those involving carcinogen-bioactivating CYP-enzyme changes 16,17. Results and Discussion Our study stemmed from the observation that vitamin E treatment of the human non-tumorigenic prostate epithelial RWPE-1 cell line induces the gene expression of P450 enzymes such as CYP1A1 (activating, for example, polychlorinated biphenyls, aromatic amines, PHAs and alkylnitrosamines), CYP1A4 (activating polycyclic

Oxidative Stress in Non-alcoholic Fatty Liver Disease. An Updated Mini Review

“…Some still unsolved safety concerns should be considered as well. Vitamin E, in fact, has been suspected to have a dichotomous suppressive and promoting activity with respect to tumorigenesis [e.g., cocancerogenic in prostate cancer; (25,129)] possibly explainable by still poorly studied host gene-supplement interactions (130). In our opinion, further carefully designed studies are still necessary for substantiating this view and supporting optimum procedures in terms of both efficacy and safety profiles.…”

Vitamin and Mineral Supplementation for β-Thalassemia During COVID-19 Pandemic

“…The risk was increased by 17% at 7 years of median follow-up [ 40 ]. In vivo study indicated that vitamin E upregulated CYPs, including CYP1A1 and CYP1B1 which highly expressed in prostate cancer, increased ROS production and led to the mutation of prostate cells [ 41 ]. Therefore, males with prostate hyperplasia, elevated prostate-specific antigen or history of prostate cancer should be cautious when consuming high dose of vitamin E [ 42 ].…”

Alpha‐ and gamma‐tocopherol levels in human semen and their potential functional implications

“…This effect is probably due to the hepatic α‐TOH transfer protein, which preferentially incorporates α‐TOH into the plasma, as well as increasing hepatic catabolism of γ‐TOH to γ‐carboxyethyl‐hydroxychroman (γ‐CEHC) (γ‐TOH water‐soluble metabolite) (Devaraj, Leonard, Traber, & Jialal, ). Finally, it must be considered that α‐TOH, as synthetic isomer of vitamin E, has been reported to act as a co‐carcinogen in in vitro model systems (Vivarelli et al, ) in support of the hypothesis that α‐TOH might sustain prostate tumour growth (Klein et al, ).…”