METABOLISM AND DRUG INTERACTIONS

Drug metabolism and vitamin E

α-tocopherol modulates the gene expression of a subset of hepatic proteins involved in xenobiotic metabolism and excretion (Phases I, II, and III).
Phase I reactions - many compounds are converted to more water-soluble compounds

(You will read more about Phase I of Xenobiotic metabolism in the e-lectures Cancer Biology and Food Toxicology.)

Induction by α-tocopherol of these pathways warrants further experimentation as alterations in xenobiotic metabolism and disposition could alter the efficacy of therapeutic drugs. In addition, these proteins are involved in the metabolism of phytochemicals, such as phylloquinone, tocotrienols and alkylresorcinols:

• phase I CYPs (cytochrome P450 mixed function oxidases)
• phase II SULTs (sulfotransferases)
• phase II GSTs (glutathione S-transferases)

Thus, induction of this battery of genes by α-tocopherol may alter the metabolism of other phytochemicals.

• Tocopherols are metabolised by CYP (cytochrome P 450) system to e.g. CEHC - carboxyethyl hydroxychroman
• CYPs (Cyp3A4, and Cyp3A5) which metabolise 60% of drugs are induced by SXR (steroid and xenobiotic receptor - in rodents PXR)
• SXR is a drug-activated nuclear receptor that is also activated by all tocopherols
• All this suggests that tocopherols may interfere with drug metabolism (xenobiotic metabolism)
• Inappropriate intake and type of vitamin E may disturb optimum xenobiotic metabolizing enzymes via SXR and may thus weaken therapeutic efficacy of drugs

Table
Human drug disposition genes regulated by SXR
Specific role in vitamin E metabolism is also shown.