- Message from Chair
- TOXI Program at National Meeting in Washington DC
- Research Highlight: The mechanism of action of dithiolethione cancer preventives; a journey on the frontier of the chemistry and biology interface
- TOXI Elections
- TOXI planning session
- Call for Candidates-U.S. Pharmacopeia
Message from the Division Chair, Professor Lisa A. Peterson
Fall National Meeting in Washington DC. TOXI division programming in Washington was very successful. The sessions were well attended and we had many interesting contributions from the membership. Please see our Facebook for numerous pictures from the meeting. A big THANK YOU to our program chair, Kaushik Mitra, and Stephen Doster for the smooth execution of the program as well as Shana Sturla for her successful meeting grant application to the National Cancer Institute and Paul Henderson for his successful Innovation grant. I would also like to acknowledge our financial sponsors: The National Cancer Institute , Merck , Pfizer, Bristol Meyers Squibb, Boehringer Ingelheim, Novartis, and Abbott.
Founder's Award Symposium. 
We had our second annual Founder's Award Symposium organized by the Founder's Award winner, Stephen Hecht. The theme of this outstanding symposium was "Chemical Toxicology and Human Cancer." Nominations are now open for the 2010 Founder's Award. This annual award is designed to recognize a TOXI division member for their research contributions in the field of chemical toxicology. Please send nominations to Stephen Hecht (hecht002@umn.edu), chair of the Awards committee.
Executive and Business Meetings in Washington. The majority of executive committee meeting was spent discussing the outcome of the strategic planning session (see below) and the current state of the division. I am happy to report that the state of the division is strong. Our financial situation has stabilized thanks to the structures put in place by Fred while he was chair and the efforts of the Finance Committee (chaired by Pete Dedon) as well as individuals willing to write grants to support programming (Shana Sturla and Paul Henderson). I am excited about our future. Our strength continues to be our involved and dedicated membership. I was especially pleased to see the strong turnout at the business meeting (>40 people).
Strategic Planning. In the two days preceding the meeting in August, 11 TOXI members met to develop a strategic plan for the next three years. Members of the strategic planning team were: myself, Andrea Cumming, Scott Daniels, Peter Dedon, Fred Guengerich, Dan Liebler, Dick Loeppky, Kaushik Mitra, Trevor Penning, Tom Spratt, and Shana Sturla. I would like to thank these individuals for their willingness to take time out of their busy schedules to participate in this important activity. I also want to thank all the members who responded to our survey. These data were crucial for the planning process.
One of the first outcomes of this meeting was a revision of our mission statement to more accurately reflect the scientific interests of our membership. The new mission statement, approved by the executive committee and to be voted on by the membership pending approval by the National ACS Bylaws Committee, is to improve human health and public welfare by promoting the understanding of chemical mechanisms that govern disease processes and the toxicity of drugs, environmental agents, and endogenous chemicals. We agreed on three goals for the next three years: Goal 1: to expand active membership to include all relevant constituency groups; Goal 2: To ensure sustainable funding adequate for TOXI activities; and Goal 3: To have our expertise in chemical mechanisms of toxicology and disease processes recognized by ACS and members and to use our expertise to advance the mission of the division. For each goal, we have developed discrete objectives. The details of these objectives will be outlined in future newsletters. To accomplish these goals, we will be forming several new committees such as a professional development committee, a networking committee, an Endowment Fund board, a Division Income committee and a publicity committee. Please let me know if you are willing to serve on any of these committees (peter431@umn.edu).
Programming for 2010 Fall National Meeting in Boston. Program Chair, Kaushik Mitra.( Kaushik_mitra@merck.com) is now taking suggestions for next Fall's annual meeting in Boston. The programmatic theme for this meeting is "Preventing and Combating Disease" so we are particularly interested in directing the Division's program to target this theme. Our Program chair-select, Shana Sturla (sturl002@umn.edu) is also soliciting ideas for the 2011 meeting in Denver. The programmatic theme for this meeting will be Chemistry of Air, Space, and Water.
In conclusion , I would like to thank everyone who has contributed to the division's activities. This includes all the individuals who participate as elected officers or on the various committees as well as the members who attended and participated in the communication of great science at the National meeting. It has been fun to work with so many dedicated individuals.
Lisa
American Chemical Socienty National Meeting
Washington DC, August 15-20, 2009
Emminent TOXI members recognized as American Chemical Society Fellows
The new ACS fellows program honored its inaugural class of 162 members this year. The program honors ACS members who have contributed to "Excellence in Science" and "Outstanding Service to ACS." Neal Castagnoli, Fred Guengerich, Steve Hecht, and Richard Loeppky were amongst the scientists recognized with this honor. In addition to their exceptional research accomplishments, these individuals have been instrumental in the establishment and continued success of the Division of Chemical Toxicology.
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| Stephen Hecht | F. Peter Guengerich | Neal Castognoli Jr | Richard Loeppky |
The ACS intends that this program will truly honor scientists who have achieved excellence in chemistry as well as within the society. Read more at: http://www.cen-online.org/acsnews/87/8730acs.html. As described on the ACS webite:
The ACS Fellows Program was created by the Board of Directors in December 2008 “to recognize members of the American Chemical Society for outstanding achievements in and contributions to Science, the Profession, and the Society.” Unlike ACS national awards, the distinguished honor of a Fellows designation will go to those who have distinguished themselves in multiple areas, including promoting the science, the profession, and service to the American Chemical Society. Ultimately, the body of Fellows is intended to reach approximately 1-2% of ACS membership.
Nominations for the second class of ACS Fellows will open in the first quarter of 2010. The nominations process is outlined on the National ACS website. Please send nominations of TOXI members to Stephen S. Hecht (hecht002@umn.edu), chair of the Awards committee. The committee will determine which four applications will be submitted from the division. Now is the time to honor your mentors. Nominate them for this honor.
Young Scientist Award Winners
The following students and post docs were winners of the Young Investigator Awards.
Oral Presentations
1 Detection of ethylene dibromide mediated DNA-adducts of O6-alkylguanine-DNA alkyltransferase. Goutam Chowdhury, Anthony E. Pegg, and F. Peter Guengerich
2 (tie) Transnitrosation of thioredoxin by S-nitrosoglutathione in vitro. Charles G. Knutson, Katherine T. Barglow, Michael A. Marletta, John S. Wishnok, and Steven R. Tannenbaum.
2 (tie) Reversible quinone methides alkylation of DNA. Huan Wang and Steve E. Rokita
Student Poster Presentation
1 Tetrabromobisphenol A interferes with the immune function of human natural killer cells Esther Caroline Kibakaya, Krishna Stephen, and Margaret M. Whalen
2 Chemical aspects of acylfulvene bioactivation to a cytotoxic reactive intermediate Kathryn E. Pietsch, Xiang Yu, James F. Neels, Jiachang Gong, and Shana J. Sturla
Post-doc Poster Presentation
1 Inflammation-induced changes in the serum metabolome Erin G. Prestwich, I. Ramesh Babu, Koli Taghizadeh and Peter C. Dedon
2 Effects of base sequence context on the nucleotide excision repair of AF- and AAF-C8-dG adducts in NarI sequence duplexes Lu Zhang, Konstantin Kropachev, Marina Kolbanovskiy, Alexander Kolbanovskiy, Lihua Wang, Suse Broyde, and Nicholas E. Geacintov
Pictured are (from left to right) are Kaushik Mitra, Charles Knutson, Esther Kibakaya, Kathryn Pietsch, Erin Prestwich, Lihua Wang, Goutam Chowdhury, and Lisa Peterson
Presentations on-line
Many presenters have placed their seminars and poster presentations online. Go to http://members.acschemtox.org to view the presentations. use your email address as your username and ACS number as your password. (Try with and without the leading zeros).
2009 TOXI Young Investigators Travel Grants Program
With the support of a grant for the National Cancer Institute, the Division of Chemical Toxicology awarded travel grants to student and postdoctoral researchers to attend the National ACS meeting. The five awardees were Timothy Feliciano, an undergraduate at California State University at Long Beach, graduate students Kathryn Pietsch (University of Minnesota) and Jason Berninger (Baylor University), and postdocs Rasulev Bakhtiyor (Jackson State University) and Manjori Ganguly (University of Pittsburg).
A goal of the program was to promote participation from first-time meeting attendees, researchers new to the division, and those for whom the award would have a significant impact in enabling the researcher to attend the meeting. The awardees were selected from a competitive application process by a panel of TOXI members. Each presented their original research at the meeting, and their science and experiences will be highlighted in future newsletters. Congratulations to the awardees!
Pictures from the ACS Meeting are on Facebook
Pictures from the ACS Meeting on Facebook. Pleae look and upload your own photos!
The Nominations Committee (Larry Marnett, chair, Kent Gates and Pete Dedon) have put together a strong slate of candidates for our Fall election involving Treasurer, Secretary, Member at large for the Executive Committee, and Nominations Committee. Your involvement in the Division is crucial for our success. The election will be held electronically during October.
TOXI had a strategic planning session on the Thursday and Friday before the ACS Meeting in DC. Participants included many of the current officers and an old-timer and a graduate student. The process began prior to the meeting by analyzing the current situation of the Division. This process included the survey that ~200 members participated in this spring. The Current Situation Report was complied by Bernard Renoylds, who lead the session. At the meeting we continued this discussion and identified Strengths, Weaknesses, and Opportunities for TOXI.
The next phase of the Strategic Planning Session began with the participants each identifying how we would envision TOXI three years from now, and how we got there. During this phase each particpant developed 5-7 ideas. These ideas were organized in such a way that the 60 ideas were placed into six categories. From these six categories, three were chosen as the basis of our strategic plan. Below is a summary of our Strategic Plan.
Strategic Goals
- To expand active membership to include all relevant constituency groups.
- Increase membership by 30% by 2013 by identifying scientists who perform TOXI research but do not know us.
- Develop professional skills and career development programs to increase our appeal to graduate students, post-docs and assistant professors.
- Develop a new social/ professional networking service.
- To ensure sustainable funding for TOXI activities.
- Create an Endowment Fund for the Founders' Award.
- Increase our revenues for our other divisional activities
- To be internationally renowned for our expertise in chemical mechanisms for toxicology and disease processes.
- Redefine our research focus on "chemical mechanisms of toxicology and disease processes"
- Communicate the relevance and scope of the division's scientific focus to ACS and its members.
- Project an identity unique to the division and obvious to the scientific public, members, of other societies, and establishes the division's leadership, presence and impact.
The Final Strategic Plan is still being written. In the near future we will ask members to change our bylaws to accomplish these goals. Sepcifically, we want ot change our Mission Statement and Create a new office of Treasurer-Elect.
Research Highlight: The mechanism of action of dithiolethione cancer preventives; a journey on the frontier of the chemistry and biology interface.
Dithiolethiones are a class of organosulfur compounds that possess chemopreventive characteristics that involve the induction of cytoprotective proteins. The raise in steady state levels of cytoprotective proteins enhances the metabolism and detoxification of carcinogens. The parent dithiolethione pharmacophore 3H-1,2-dithiole-3-thione (D3T), seen below, is a natural product found in some types of cabbage, and various synthetic derivatives have been formulated that also possess chemopreventive properties.
Cytoprotective protein levels are controlled at the transcriptional level by a 41 base pair sequence known as the antioxidant response element (ARE). Transcription factor NF-E2-related factor-2 (Nrf2) binds the ARE and enhances the transcription of downstream genes. Under basal cellular conditions Nrf2 is located in the cytosol and is bound to the kelch-like ECH-associated protein 1 (Keap1), where it is targeted for ubiquitination and degradation. Electrophilic and oxidative stress triggers Nrf2 translocation to the nucleus, where it forms heterodimers with small Maf proteins, thus initiating the transcription of the cytoprotective genes that it controls.
The mechanism by which dithiolethiones activate Nrf2 in mammalian cells involves reductive metabolism, resulting in the scission of the S1-S2 bond. These reductive metabolites can reduce molecular oxygen, forming superoxide radical anion. Subsequent dismutation of the superoxide anion forms hydrogen peroxide, which is a pivotal second messenger for dithiolethione enzyme induction potency. .This paradigm is consistent with the general hypothesis that oxidants such as hydrogen peroxide encumber Keap1, a negative regulator of Nrf2, thus enhancing Nrf2 activity.
I was interested in understanding how oxidative processes modulate the derepression of Nrf2 by Keap1. Oxidative bursts are known to temporally alter the glutathione (GSH/GSSG) redox couple resulting in protein glutathionylation (Type 1 modification) and protein disulfide closure (Type 2 modification). Thus I investigated Keap 1 modification, by varying the GSH/GSSG ratio in a physiologically relevant range. Type 1 modifications were detected at Cys77, Cys297, Cys319, Cys368 and Cys434 of Keap1, while Type 2 modifications involving Cys23-Cys38, Cys257-Cys297 and Cys319-Cys319 were observed. These span several functional domains of Keap1: the dimerization domain, the central linking region, and the kelch domain. Through mathematical modeling, Type 1 disulfides Cys368 and Cys434 appear to alter the structure of the kelch domain, i.e. the Nrf2-binding domain, of Keap1. Hypersensitive cysteine residues in Keap1 can also be modified directly by low concentrations of H2O2 and may cause the observed activation of Nrf2. These data suggest a role for oxidative stress in the dithiolethione-mediated induction of cytoprotective enzymes and chemopreventive activity.
Call for Candidates-U.S. Pharmacopeia
At the August ACS meeting, the TOXI Division was invited to a U.S. Pharmacopeia breakfast and I (Immediate Past-Chair) attended. This was a very informative meeting for me, and I believe that members of our Division can play an important role in matters that affect our society by participating.
The U.S. Pharmacopeia is a non-governmental, not-for-profit organization that has standard-setting authority for all prescriptions and over-the-counter medicines and health care products manufactured or sold in the United States. This includes dietary supplements and veterinary products. Please see the attached pdf and also refer to their website, www.usp.org. The mission is to improve the health of people around the world through public standards. As many of you are aware, there are many problems in this area, e.g. melamine contamination. Many of our Division members are expert in the use of analytical chemistry and also very cognizant about toxicological principles and issues of dose.
The U.S. Pharmacopeia (USP) is calling for nominations for candidates for the 2010-2015 USP Council of Experts, Expert Committees, and Expert Panels. As you will see, many of these are relevant to our interests. I told the USP members that I would push their case to our members. Please give this very serious consideration. Your assistance could really make a difference.
TOXI Activities in the News
A recent C&E News article describes the special issue of Chemical Research in Toxicology published this past February regarding human metabolites in safety testing, and the follow-up ACS symposium on the topic organized by Fred Guengerich and Nicholas Meanwell. Read More at:
Troublesome Drug Metabolites Published: August 31, 2009 Volume 87, Number 35 pp. 27 - 28 Article Location: http://pubs.acs.org/cen/email/html/8735sci1.html >From Chemical & Engineering News http://www.cen-online.org A service of the American Chemical Society.