Annual Meeting of 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.

View full abstract

Show abstractHide abstract

It is estimated that up to 12 million Americans have food allergies, which occur when the immune system mistakenly responds to a food protein believing it to be harmful. Not all proteins are allergens, and the properties that make some `novel proteins' allergenic are not completely understood. There is currently no single endpoint that can predict the allergenic potential of a protein, and a weight of evidence approach is utilized. This presentation will review the current state-of-the-science of this approach by focusing on the safety assessment of genetically modified crops which includes the evaluation for protein allergenicity. Specifically, this approach, as defined by the Codex Alimentarius commission, evaluates: whether the gene source is allergenic; sequence similarity to known allergens; and protein resistance to pepsin in vitro. If concerns are identified, serological studies may be necessary to determine if a protein has IgE binding similar to known allergens. Since there was a lack of standardized/validated methods to conduct the allergenicity assessment, a multi-sector, multi-national committee was assembled in 2000 under ILSI HESI to address this issue. Over the last eight+ years, the Protein Allergenicity Technical Committee (PATC) has convened workshops and symposia with allergy experts and government authorities to refine methods that underpin the assessment for potential protein allergenicity. This presentation will highlight this ongoing effort, summarizing workshops and formal meetings, referencing publications and describing outreach activities. The purpose is to outline the `state-of-the-science' in predicting protein allergenicity in the context of current international recommendations for novel protein safety assessment, and to identify approaches that can be improved and future research needs.

View full abstract

Register with J-STAGE for free!