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Nutrient Metabolism

Long-Chain Carboxychromanols Are the Major Metabolites of Tocopherols and Tocotrienols in A549 Lung Epithelial Cells but Not HepG2 Cells^1,2

Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853

³To whom correspondence should be addressed. E-mail: rsp3{at}cornell.edu.

Human lung type II cell derived A549 epithelial cancer cells and HepG2 hepatocytes constitutively express cytochrome P4504F2, a P450 we previously identified as a tocopherol--hydroxylase. To determine if A549 cells would metabolize tocochromanols via the -hydroxylase pathway, we compared the metabolism of tocopherols (-, -, -TOH) and tocotrienols (-, -, -T3) in these 2 cell lines. Cultures were incubated with -, -, or -TOH, or the analogous T3s, and synthesis of their metabolites quantitated by GC-MS. A549 cells metabolized all tocochromanols 2–3 times more extensively than HepG2 cells (P < 0.001) except -TOH, a difference not related to cell uptake of substrate but rather was reflective of greater microsomal TOH--hydroxylase enzyme activity. Notably, 9'-carboxychromanols were the major metabolites of all - and -TOHs and T3s in A549 cultures, whereas 3'- and 5'-carboxychromanols predominated in HepG2 cultures. Accumulation of 9'-carboxychromanols in A549 cultures was due to their inefficient conversion to 7'-carboxychromanols relative to HepG2 cells. Sesamin inhibited tocochromanol metabolism in both cells types, and neither cell type exhibited evidence of alternative (sesamin-insensitive) pathways of metabolism. TOH--hydroxylase activity was undetectable in rat primary lung type II cells, suggesting that expression of activity was associated with transformation of normal type II cells to cancer cells. Long-chain carboxychromanol metabolites of -TOH and other forms of vitamin E can be biosynthesized in A549 cultures for assessment of their biological activity, including their potential inhibition of synthesis of inflammatory mediators.

KEY WORDS: • tocopherols • tocotrienols • metabolism • -oxidation • A549 • HepG2

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