Response

Extract

We welcome the many efforts to provide mechanistic explanations for the now well-documented adverse effects of beta-carotene and the beta-carotene/ retinyl palmitate combination in the large-scale ATBC and CARET trials of chemoprevention of lung cancer ( 1 , 2 ). These findings have stimulated new laboratory studies of the effects of beta-carotene by CARET investigators, CARET collaborators (N. Krinsky, W. Blaner), and others, which is a desirable result of definitive prevention trials of scientific hypotheses. When ATBC, CARET, and the Physicians' Health Study were initiated in the early 1980s, all- trans beta-carotene was by far the most promising candidate chemopreventive agent, based on epidemiologic, animal, and biochemical knowledge; these trials were designed to test that hypothesized benefit.

Interest in other isomers and other carotenoids is still speculative. Synthetic beta-carotene is indistinguishable from beta-carotene in fruits and vegetables (90% all- trans ; the rest, 9- cis and 13- cis ), and serum beta-carotene after administration of algal beta-carotene (half 9- cis , half all-trans) is almost entirely all- trans ( 3 , 4 ). Based on detailed 13 C-labeling studies ( 5 ), the algal results almost surely reflect in vivo isomerization from 9- cis to all- trans and lack of absorption of 9- cis from the intestine (Blaner W: personal communication), rather than consumption of 9- cis in reducing the oxidation of lipids, based on nonspecific assays of such lipid fractions ( 4 ). Furthermore, while 9- cis appears to be a more potent antioxidant dissolved in organic solvents in vitro, there is no evidence that this is so in vivo, especially in lipoprotein particles or when taken up into cells (Blaner W: personal communication). Nevertheless, interest continues to grow in the 9- cis isomer, which can arise in tissues at 37 °C from all- trans ( 6 ) and which can be converted via 9- cis retinol dehydrogenase to the highly active retinoid 9- cis -retinoic acid (Swisshelm K, Paik J, Blaner W: unpublished data). Challem's concern that our moderate doses of beta-carotene and retinol caused liver damage in persons in the high percentiles of alcohol intake can be dispelled by CARET data. In liver disease associated with long-term high intake of ethanol and hypervitaminosis A (or other causes), serum retinol levels drop markedly as a result of reduced hepatic secretion of the retinolbinding protein ( 7 ). CARET data show no decreases in serum retinol levels and no increases in levels of aspartate aminotransferase or alkaline phosphatase in active versus placebo groups in the highest sex-specific quartile ( Table 1 ) or in the even higher subgroups with alcohol intake of greater than 30 or 50 g/day.