title: Long-chain carboxychromanols are the major metabolites of tocopherols and tocotrienols in A549 lung epithelial cells but not HepG2 cells.
abstract: 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-omega-hydroxylase. To determine if A549 cells would metabolize tocochromanols via the omega-hydroxylase pathway, we compared the metabolism of tocopherols (alpha-, gamma-, delta-TOH) and tocotrienols (alpha-, gamma-, delta-T3) in these 2 cell lines. Cultures were incubated with alpha-, gamma-, or delta-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 alpha-TOH, a difference not related to cell uptake of substrate but rather was reflective of greater microsomal TOH-omega-hydroxylase enzyme activity. Notably, 9'-carboxychromanols were the major metabolites of all gamma- and delta-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-omega-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 gamma-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.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Cha-Sook
authors.initials: CS
authors.lastname: You
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sontag
authors.forename: Joy E
authors.initials: JE
authors.lastname: Swanson
authors.forename: Robert S
authors.initials: RS
authors.lastname: Parker
mesh_terms: D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D008175:Lung Neoplasms; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism; D051381:Rats; D020545:Respiratory Mucosa; D024505:Tocopherols / Q000378:metabolism*; D024508:Tocotrienols / Q000378:metabolism*
chemical_list: D024508:Tocotrienols; D006899:Mixed Function Oxygenases; C479073:tocopherol-omega-hydroxylase; D024505:Tocopherols