The enigma of beta-carotene in carcinogenesis: what can be learned from animal studies

Our plain-English summary of The enigma of beta-carotene in carcinogenesis: what can be learned from animal studies, by R.M. Russell (The Journal of Nutrition, 2004).

The study

• Author: R.M. Russell
• Journal: The Journal of Nutrition
• Published: 2004;134(1):262S-268S
• Type of article: Review
• Cited by: 73 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Beta-carotene and other carotenoids have been thought to have anti-cancer activity, either because of antioxidant activity or because of their ability to be converted to vitamin A. Nevertheless, two large scale intervention studies in humans using high doses of beta-carotene found that beta-carotene supplementation resulted in more lung cancer rather than less lung cancer among smoking and asbestos exposed populations. Studies conducted in the ferret have elucidated molecular mechanisms behind this observation, in that high-dose beta-carotene and smoke exposure in these animals leads to squamous metaplasia, a pre-cancerous lesion in the lung. High dose beta-carotene in the smoke exposed animals was found to give rise to a number of transient oxidative metabolites, which include P450 enzymes that result in the destruction of retinoic acid, and diminished retinoid signaling, and enhanced cell proliferation. In addition, eccentric cleavage beta-carotene metabolites facilitate the binding of smoke derived carcinogens to DNA. In other ferret studies low dose beta-carotene smoke exposure provided mild protection against squamous metaplasia. Thus, it appears that the explanation of the apparent paradoxical effects of beta-carotene on lung cancer is related to dose. The metabolism and breakdown of natural products should be thoroughly investigated in animal models before embarking on large scale intervention trials, particularly when using unusually high doses that greatly exceed normal dietary levels.

In plain English

This symposium paper reviewed ferret and laboratory experiments from the author's own laboratory on beta-carotene and the lung. The work was prompted by human trials run by other researchers, including CARET, which gave beta-carotene and retinol to smokers and/or asbestos-exposed workers. The ferret experiments did not involve asbestos. Ferrets, six per group, received beta-carotene at a dose equivalent to 30 mg a day in humans, cigarette smoke, both, or neither, for six months. All six ferrets given high-dose beta-carotene alone showed abnormal growth of lung cells. All six given high-dose beta-carotene plus smoke had the most severe changes, including squamous metaplasia, which the author described as a pre-cancerous lesion. A marker of cell growth rose 1.8-fold and 3.7-fold in these two groups. Lung retinoic acid, a form of vitamin A, was lower in all three treated groups than in controls. In a later study, a low dose (equivalent to 6 mg a day) produced no lesions. Squamous metaplasia was seen in none of the smoke-exposed ferrets given the low dose, compared with 2 of 6 ferrets given smoke alone. The author concluded that dose counts.

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: Symposium paper reviewing the author's laboratory's ferret (animal) and test-tube experiments. The work was prompted by human trials run by others, including CARET in smokers and/or asbestos exposed workers.
• Who was studied: Domesticated ferrets, six per group, assigned to groups with or without beta-carotene and with or without cigarette smoke exposure for six months
• Exposure: Ferrets received beta-carotene by mouth at a high dose equivalent to 30 mg a day in humans; a later study compared this with a low dose equivalent to 6 mg a day. Cigarette smoke was given as 10 cigarettes over 30 minutes, twice each morning and twice each afternoon. The ferret experiments involved no asbestos.
• Main results:
  • All six ferrets given high-dose beta-carotene alone showed localized proliferation of alveolar cells with keratinized squamous epithelium.
  • All six ferrets given high-dose beta-carotene plus smoke showed the most severe focal proliferation, squamous metaplasia and destruction of alveolar walls.
  • Expression of the cell-proliferation marker PCNA rose 1.8-fold in beta-carotene-supplemented ferrets not exposed to smoke, and 3.7-fold in beta-carotene-supplemented ferrets exposed to smoke.
  • Lung retinoic acid levels were lower than in controls in the smoke-exposed, beta-carotene-supplemented, and combined groups. Retinoic acid was not detected in either smoke-exposed group.
  • In test-tube incubations, formation of beta-carotene breakdown products (apo-carotenals) was threefold higher with lung extracts from smoke-exposed ferrets than from unexposed ferrets.
  • c-Fos expression was up-regulated 3- to 4-fold in beta-carotene-supplemented, smoke-exposed ferrets compared with controls.
  • In the low- versus high-dose study, keratinized squamous metaplasia was found in none of the smoke-exposed ferrets given low-dose beta-carotene, compared with 2 of 6 ferrets exposed to smoke alone.
• The authors' conclusion: The author concluded that dose counts: in the animal model, high-dose beta-carotene led to lung pathology with or without smoke exposure, and the pathology was worse with smoke. The author also concluded that natural products should be studied at various doses in animal models before large-scale intervention trials.
• Limitations the authors state:
  • The author stated that no animal model perfectly replicates the human situation.

Topics

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

Related studies

• Chemoprevention of cancer: lessons to be learned from beta-carotene trials — H. Vainio (2000)
• Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke — X.D. Wang, C. Liu, et al. (1999)
• Effects of 6-month daily supplementation with oral beta-carotene in combination or not with benzo[a]pyrene on cell-cycle markers in the lung of ferrets — A. Fuster, C. Picó, et al. (2008)
• beta-Carotene fails to act as a tumor promoter, induces RAR expression, and prevents carcinoma formation in a two-stage model of skin carcinogenesis in male Sencar mice — R.M. Ponnamperuma, Y. Shimizu, et al. (2000)
• No dose-dependent increase in fracture risk after long-term exposure to high doses of retinol or beta-carotene — G.L. Ambrosini, A.P. Bremner, et al. (2013)
• Beta-carotene metabolites enhance inflammation-induced oxidative DNA damage in lung epithelial cells — Y.G. van Helden, J. Keijer, et al. (2009)

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