主催: The Japanese Society of Toxicology
There is considerable variation in the responses to drugs and other xenobiotics.
One reason for this variation is that concomitant exposure to drugs and other chemicals can alter the metabolism of chemicals by inducing the cytochrome P-450 enzymes (Cyps) in livers. It has been determined that xenobiotic activation of one of three transcription factors (AhR, CAR, and PXR) is responsible for the induction of Cyps. In addition to Cyps, there are other phase-I drug metabolizing enzymes, as well as phase-II conjugating enzymes that are important in the metabolism of xenobiotics. Transporters are important in the movement of chemicals into and out of cells and thus also affect the disposition of xenobiotics. This lecture will demonstrate that many of these enzymes and transporters can be induced by chemical activation of the three transcription factors noted above, as well as PPARa and Nrf2. The availability of mice engineered to lack each of these transcription factors has helped tremendously to understand the mechanisms of how xenobiotics increase the expression of uptake transporters, cytochrome P-450s, glucuronosyltransferases, glutathione transferases, efflux transporters, etc. This lecture will summarize the state-of-the-art knowledge of how activation of various transcription factors alter the pharmacokinetics of xenobiotics by modifying phase I, phase II, and transporters in liver and intestine.
