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.
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.
Dosing and safety monitoring for phase I clinical trials is planned with careful attention to the findings during animal toxicity studies but drug development compounds are still frequently dropped in early phase development for unanticipated safety issues. This presentation aims to illustrate both the limits of applying preclinical safety findings to clinical development and the different approaches taken to evaluating data taken by preclinical and clinical scientists. Several examples of compounds dropped for safety reasons during early phase I clinical development are examined for preclinical correlates of the clinical safety findings which eventually led to discontinuation of development. The examples are presented jointly and discussed by a preclinical toxicologist and a physician. Examples are given of compounds where the adverse reaction which led to discontinuation of development was observed in animal studies but occurred at much lower exposure levels in man than was predicted by animal data and of compounds that were discontinued for reactions in man that were not at all evident during preclinical testing. In each case the findings are examined with attention to the preclinical and clinical pharmacokinetic findings and putative mechanisms of action of the adverse reaction observed.
発生毒性ゲノミクス研究には発生生物学の研究成果を前提にしたメカニズムベースのアプローチが多い。これは，すでに多くの器官において形態形成過程でキーとなる遺伝子あるいは遺伝子カスケードが明らかになっている背景があるからであり，通常，ターゲットとする器官の形態形成が行なわれる時期および部位において特異的に変動する遺伝子を網羅的に解析するアプローチがとられる。我々もバルプロ酸とその誘導体を用いてマウス胚の神経管閉鎖異常に関して時期および部位特異的に変動する遺伝子を見い出し，神経管形成メカニズムと神経管閉鎖異常関連遺伝子との関連性を明らかにしようとしている。さらにEPAのNCCT (National Center for Computational Toxicology) を中心として欧米で進められているv-Embryoプロジェクト (The Virtual Embryo Project) は既知の形態形成遺伝子制御をベースに発生毒性をin silicoで解析しようと試みている。一方，発生毒性の代替法としてマウスES細胞の心筋分化系が欧州ECVAMの共同研究によって検証されてからすでに久しい。この研究成果は，発生毒性のリスク検出には発生の時期および部位特異性を考慮する必要性について疑問を投げかけているように感じる。つまり，ES細胞に限らず，初期胚あるいは多分化能をもつ細胞系を用いて変動遺伝子を解析することによって化合物の催奇形性をスクリーニングできる可能性を示唆している。発生毒性リスク評価を単純な試験系と質の高いインフォマティクスによって達成することが今後の挑戦課題ではないだろうか。これらの現状から医薬品開発におけるスクリーニング段階と開発段階での発生毒性ゲノミクスのインプットについての展望を述べてみたい。
Worldwide attention has recently been focused on a group of persistent organic pollutants known as the perfluorinated compounds (PFCs). This class of compounds includes perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) and a large number of other structurally related compounds that have been used in a wide range of industrial and consumer applications for the past 5 decades. Concern about these compounds has increased due to a growing number of studies which indicate that some of these compounds are toxic, bioaccumulative, and persistent in the environment. Moreover, the mean half-lives of PFOS and PFOA in humans have been estimated to be 5 and 4 years, respectively. Recent advances in analytical chemistry have made it possible to measure these compounds in environmental and biological matrices, but the sources of human exposure remain poorly described. This presentation will review some of the latest studies conducted by the USEPA and others to describe our current understanding of how humans are exposed to these compounds. A review of the most recent studies of potential human health effects will also be included. Disclaimer: Although this work was reviewed by EPA and approved for publication, it may not necessarily reflect official Agency policy.
The perfluoroalkyl acids (PFAAs) are a family of organic chemicals consisting of a perfluorinated carbon backbone (4-12 in length) and an acidic functional moiety (carboxylate or sulfonate). These compounds have excellent surface-tension reducing properties and have numerous industrial and consumer applications. However, they are chemically stable, persistent in the environment, ubiquitously distributed, and present in humans and wildlife. The rates of PFAA elimination and their body burden accumulation appear to be dependent on carbon-chain length, functional moieties, and animal species. Recent laboratory studies have indicated a host of adverse health effects associated with exposure to PFAAs; these include carcinogenicity, hepatotoxicity, developmental toxicity, immunotoxicity, neurotoxicity and endocrine disruption. The modes of PFAA actions are not well understood, but are thought to involve in part, activation of nuclear receptor molecular signals. In general, extent of the PFAA toxicity corresponds to chain lengths of the chemical, which likely reflects the pharmacokinetic properties of these fluorochemicals as well as their potency of actions. This abstract does not necessarily reflect US EPA policy.