ß-Carotene and Lung Cancer in Smokers: Review of Hypotheses and Status of Research

Abstract

A number of epidemiological studies have reported associations of β-carotene plasma levels or intake with decreased lung cancer risk. However, intervention studies in smokers have unexpectedly reported increased lung tumor rates after high, long-term, β-carotene supplementation. Recently, detailed analyses by stratification for smoking habits of several large, long-term intervention or epidemiological trials are now available. The ATBC study, the CARET study, the Antioxidant Polyp Prevention trial, and the E3N study provide evidence that the adverse effects of β-carotene supplementation are correlated with the smoking status of the study participants. In contrast, the Physician Health Study, the Linxian trial, and a pooled analysis of 7 epidemiological cohort studies have not supported this evidence. The ferret and A/J mouse lung cancer model have been used to investigate the mechanism of interaction of β-carotene with carcinogens in the lung. Both models have specific advantages and disadvantages. There are a number of hypotheses concerning the β-carotene/tobacco smoke interaction including alterations of retinoid metabolism and signaling pathways and interaction with CYP enzymes and pro-oxidation/DNA oxidation. The animal models consistently demonstrate negative effects only in the ferret, and following dosing with β-carotene in corn oil at pharmacological dosages. No effects or even protective effects against smoke or carcinogen exposure were observed when β-carotene was applied at physiological dosages or in combination with vitamins C and E, either as a mixture or in a stable formulation. In conclusion, human and animal studies have shown that specific circumstances, among them heavy smoking, seem to influence the effect of high β-carotene intakes. In normal, healthy, nonsmoking populations, there is evidence of beneficial effects.

Notes

^a Abbreviations are as follows: β-c, beta carotene; ATBC, Alpha-Tocopherol, Beta Carotene study; CARET, Beta-Carotene and Retinol Efficacy Trial; PHS, Physician Health Study; CVD, cardiovascular disease; NSCLC, non-small cell lung cancer.

^a Abbreviations are as follows: BW, body weight; RA, retinoic acid; RAR, RA receptor; PCNA, proliferating cell nuclear antigen; β-c, beta carotene; CYP, cytochrome p450; NNK, 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; mRNA, messenger RNA; BP, benzo[a]pyrene.