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

Our plain-English summary of Modulation of genotoxic and related effects by carotenoids and vitamin A in experimental models: mechanistic issues, by S. De Flora, M. Bagnasco, H. Vainio (Mutagenesis, 1999).

The study

• Authors: S. De Flora, M. Bagnasco, H. Vainio
• Journal: Mutagenesis
• Published: 1999;14(2):153-72
• Type of article: Review
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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 beta-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 appear to work via multiple mechanisms, which would support a potential protective role in cancer initiation and in the pathogenesis of other mutation-related diseases. These conclusions are consistent with the recognized cancer-preventive activity of these nutrients in certain animal models and with the evidence provided by observational epidemiological studies, which suggested cancer-protective effects at many sites as related to their dietary intake or plasma levels. However, all these lines of evidence and mechanistically based premises contrast with the unexpected outcome of recent clinical intervention trials, which raised the concern that supplemental use of beta-carotene and vitamin A may increase the risk of lung cancer amongst high risk individuals such as tobacco smokers and asbestos-exposed workers.

In plain English

This article was a review, not a new experiment. The authors built a database from English-language laboratory studies published up to the end of 1997. These studies tested whether carotenoids (beta-carotene and 26 others) and vitamin A compounds cause, or protect against, genetic damage in bacteria, yeast, cultured cells and rodents. The database held 489 results, 205 on carotenoids and 284 on vitamin A. Asbestos was not among the agents tested. As many as 135 negative results supported the view that these nutrients do not damage genes themselves, and nine results suggested they might. The nutrients mostly did not block chemicals that act directly (51 negative results out of 65). In most studies they did inhibit agents that need metabolic activation, such as aflatoxin B1, nitrosamines and polycyclic aromatic hydrocarbons (46 protective results out of 68 for the hydrocarbons). The authors concluded that the nutrients have antigenotoxic properties. They noted that lung cancer prevention trials, reviewed elsewhere, found small but significant increases in lung cancer among smokers and asbestos-exposed workers, and that the laboratory findings did not explain this.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published experimental (laboratory and animal) studies, compiled into a database built for this article
• Who was studied: 489 published experimental results (205 on carotenoids, 284 on vitamin A) from English-language literature up to the end of 1997, covering 67 in vitro and in vivo test systems (bacteria, yeast, cultured rodent and human cells, mice, rats, hamsters)
• Exposure: Beta-carotene, 26 other carotenoids, retinol, retinal, retinoic acid and retinyl esters, tested alone or against 69 genotoxic agents. These were 3 biological agents, 4 physical agents, 54 chemical compounds and 8 complex mixtures, such as cigarette smoke, coal dust and diesel particle extracts. Asbestos is not among the agents listed in the article's table.
• Main results:
  • Tested alone, the nutrients gave 135 negative results for causing genetic damage; only nine results suggested a genotoxic role
  • Against direct-acting chemicals, the nutrients did not inhibit genotoxic effects in 51 of 65 results (78.5%)
  • Against direct-acting cytostatic (anti-cancer drug) agents, 21 of 27 results were negative
  • Most in vitro and in vivo studies found the nutrients inhibited the genotoxicity of aflatoxin B1
  • For polycyclic aromatic hydrocarbons, 46 of 68 results (67.6%) indicated protective effects, although results from different laboratories were inconsistent
  • Retinol was effective in every study of the nitrosamines reviewed
  • The authors inferred that the main mechanism was interference with how the body metabolizes foreign chemicals
• The authors' conclusion: The authors concluded that carotenoids and vitamin A have antigenotoxic properties and share several mechanisms suggesting a possible role in cancer prevention
• Limitations the authors state:
  • The authors stated that the database does not cover all existing literature
  • Results were presented only semi-quantitatively
  • The authors attributed conflicting findings between studies to many variability factors, such as dose, test system and laboratory
  • The authors noted that the major lung cancer prevention trials with beta-carotene and/or retinol (reviewed in IARC handbooks, not part of this database) showed small but significant increases in lung cancer incidence among smokers and asbestos-exposed workers
  • The authors stated that the reviewed laboratory findings do not explain these adverse trial results

Topics

Medical terms in this study, explained in our Lexicon: Lung Cancer.

Related studies

• A global clinical view on vitamin A and carotenoids — A. Sommer, K.S. Vyas (2012)
• Research cost analyses to aid in decision making in the conduct of a large prevention trial, CARET. Carotene and Retinol Efficacy Trial — M.D. Thornquist, N. Urban, et al. (1993)
• Vitamin A and cancer prevention II: comparison of the effects of retinol and beta-carotene — N.H. de Klerk, A.W. Musk, et al. (1998)
• Vitamin A and cancer prevention I: observations in workers previously exposed to asbestos at Wittenoom, Western Australia — A.W. Musk, N.H. de Klerk, et al. (1998)
• Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease — G.S. Omenn, G.E. Goodman, et al. (1996)
• Beta-Carotene, vitamin A, and lung cancer chemoprevention: results of an intermediate endpoint study — J.W. McLarty, D.B. Holiday, et al. (1995)

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