Modulation of genotoxic and related effects by carotenoids and vitamin A in experimental models: mechanistic issues

• Published in: Mutagenesis 1999-03, Vol.14 (2), p.153-172
• Main Authors: De Flora, Silvio, Bagnasco, Maria, Vainio, Harri
• Format: Article
• Language: English
• Subjects: Animals; Anticarcinogenic Agents - pharmacology; Antimutagenic Agents - pharmacology; b-carotene; Biological and medical sciences; carotenoids; Carotenoids - pharmacology; Cell Line; Databases, Factual; Food toxicology; Medical sciences; Models, Genetic; Mutation; N-myc gene; retinal; retinol; retinyl esters; Toxicology; Ultraviolet Rays - adverse effects; vitamin A; Vitamin A - pharmacology
• ISSN: 0267-8357; 1464-3804; 1464-3804
• DOI: 10.1093/mutage/14.2.153

The mechanisms involved in the modulation of genotoxic and related effects by carotenoids and vitamin A were inferred from a critical review of an ad hoc constructed database. Almost 500 results were generated in experimental models evaluating the activity of 32 structurally, metabolically and functionally related nutrients, including β-carotene and 26 other carotenoids, retinol, retinal, all-trans-retinoic acid and retinyl esters. As many as 67 experimental test systems, either in vitro or in vivo, used a variety of cellular targets and/or end-points suggestive of distinctive mechanisms of action. The bulk of available data support the view that carotenoids and vitamin A do not induce genotoxic effects per se. Even in the absence of any genotoxic agent, these nutrients appeared, on the contrary, to display some mechanisms which play protective roles in tumor promotion and progression, such as inhibition of N-myc gene expression resulting in antiproliferative effects, up-regulation of cell-to-cell communication, an increase in connexin 43 gene expression, a decrease in the `spontaneous' cell transformation frequency and induction of differentiation in vitro. A large number of studies investigated the modulation by carotenoids and vitamin A of genotoxic and related effects produced by 69 genotoxicants, including biological agents, physical agents, chemical compounds and complex mixtures. In spite of some discrepant data, the general trend was that both carotenoids and vitamin A are poorly effective in acting as nucleophiles, nor do they appear to substantially interfere with the induction or repair of DNA damage produced by direct-acting agents. In contrast, vitamin A and carotenoids, irrespective of their provitamin A role, in most studies inhibited those genotoxicants which require metabolic activation to electrophilic derivatives in either bacterial or mammalian cells. Coupled with biochemical data, the distinctive patterns observed with genotoxic agents belonging to different chemical classes suggest a complex modulation of both phase I and phase II enzymes involved in the metabolism of xenobiotics. Furthermore, carotenoids and vitamin A shared other protective mechanisms, such as scavenging of genotoxic oxygen species, modulation of signal transduction pathways, inhibition of cell transformation induced by physical and chemical agents, and facilitation of intercellular communication inhibited by genotoxic compounds. Therefore, carotenoids and vitamin A