Stephen S. Hecht

University of Minnesota Duluth, Duluth, Minnesota, United States

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Publications (393)2452.06 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Alcoholic liver disease (ALD) is linked to binge drinking and cigarette smoking. Heavy chronic ± binge alcohol, or low-level exposures to dietary nitrosamines cause steatohepatitis with insulin resistance and oxidative stress in animal models. This study examines hepatotoxic effects of sub-mutagenic exposures to tobacco-specific nitrosamine (NNK) in relation to ALD. Long Evans rats were fed liquid diets containing 0 or 26% (caloric) ethanol (EtOH) for 8 weeks. In Weeks 3 through 8, rats were treated with NNK (2 mg/kg) or saline by i.p. injection, 3×/week, and in Weeks 7 and 8, EtOH-fed rats were binge-administered 2 g/kg EtOH 3×/week; controls were given saline. EtOH ± NNK caused steatohepatitis with necrosis, disruption of the hepatic cord architecture, ballooning degeneration, early fibrosis, mitochondrial cytopathy and ER disruption. Severity of lesions was highest in the EtOH+NNK group. EtOH and NNK inhibited insulin/IGF signaling through Akt and activated pro-inflammatory cytokines, while EtOH promoted lipid peroxidation, and NNK increased apoptosis. O(6)-methyl-Guanine adducts were only detected in NNK-exposed livers. Both alcohol and NNK exposures contribute to ALD pathogenesis, including insulin/IGF resistance and inflammation. The differential effects of EtOH and NNK on adduct formation are critical to ALD progression among alcoholics who smoke. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.
    Alcohol and alcoholism (Oxford, Oxfordshire). Supplement 01/2015; 50(2). DOI:10.1093/alcalc/agu083
  • Stephen S Hecht
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    ABSTRACT: Two of the most widely measured compounds in the urine of people who use tobacco products are cotinine, a major metabolite of the addictive constituent nicotine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of the powerful lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Thousands of analyses have been reported in the literature, carried out exclusively - to the best of our knowledge - by separate methods. In the study reported here, we have developed a sensitive, accurate, and precise liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring method for the combined analysis of total cotinine (the sum of cotinine and its glucuronide) and total NNAL (the sum of NNAL and its glucuronide). The new method quantifies naturally occurring [13C]cotinine to minimize problems associated with the vast differences in concentration of total cotinine and total NNAL in urine. This method should greatly facilitate future determinations of these important compounds.
    Analytical Chemistry 12/2014; DOI:10.1021/ac504047j · 5.83 Impact Factor
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    ABSTRACT: The metabolic fate of a compound is determined by numerous factors including its chemical structure. Although the metabolic options for a variety of functional groups are well understood, and can often provide a rationale for comparison of toxicity based on structural analogy, at times, quite minor structural variations may have major consequences for metabolic outcomes and toxicity. In this paper, the effects of structural variations on metabolic outcomes is detailed for a group of related hydroxy- and alkoxy- substituted allyl- and propenylbenzenes. These classes of compounds are naturally occurring constituents of a variety of botanical based food items. The classes vary from one another by the presence or absence of alkylation of their para-hydroxyl substituents and/or the position of the double bond in the alkyl side chain. We provide an overview of how these subtle structural variations alter the metabolism of these important food-borne compounds, ultimately influencing their toxicity, particularly their DNA reactivity and carcinogenic potential. The data reveal that detailed knowledge of the consequences of subtle structural variations for metabolism is essential for adequate comparison of structurally related chemicals. Taken together, it is concluded that predictions in toxicological risk assessment should not be performed on the basis of structural analogy only, but should include analogy of metabolic pathways across compounds and species.
    Chemical Research in Toxicology 05/2014; 27(7). DOI:10.1021/tx500109s · 4.19 Impact Factor
  • Stephen S Hecht
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    ABSTRACT: The Family Smoking Prevention and Tobacco Control Act gives the Food and Drug Administration power to regulate tobacco products. This commentary calls for immediate regulation of the carcinogenic tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) in cigarette tobacco as a logical path to cancer prevention. NNK and NNN, powerful carcinogens in laboratory animals, have been evaluated as "carcinogenic to humans" by the International Agency for Research on Cancer. NNK and NNN are present in the tobacco of virtually all marketed cigarettes; levels in cigarette smoke are directly proportional to the amounts in tobacco. The NNK metabolite NNAL, itself a strong carcinogen, is present in the urine of smokers and non-smokers exposed to secondhand smoke. Some of the highest levels of NNK and NNN are found in U.S. products. It is well established that factors such as choice of tobacco blend, agricultural conditions, and processing methods influence levels of NNK and NNN in cigarette tobacco and cigarette smoke. Therefore, it is time to control these factors and produce cigarettes with 100 ppb or less each of NNK and NNN in tobacco, which would result in an approximate 15-20 fold reduction of these carcinogens in the mainstream smoke of popular cigarettes sold in the United States.
    Cancer Prevention Research 05/2014; 7(7). DOI:10.1158/1940-6207.CAPR-14-0095 · 5.27 Impact Factor
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    ABSTRACT: This publication is the 1st in a series of publications by the Expert Panel of the Flavor and Extract Manufacturers Assoc. summarizing the Panel's 3rd re-evaluation of Generally Recognized as Safe (GRAS) status referred to as the GRASr2 program. In 2011, the Panel initiated a comprehensive program to re-evaluate the safety of more than 2700 flavor ingredients that have previously met the criteria for GRAS status under conditions of intended use as flavor ingredients. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics, and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances as flavoring ingredients are evaluated. The group of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances was reaffirmed as GRAS (GRASr2) based, in part, on their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic studies and the lack of significant genotoxic and mutagenic potential.
    Journal of Food Science 04/2014; 79(4). DOI:10.1111/1750-3841.12407 · 1.79 Impact Factor
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    ABSTRACT: Diets containing either freeze-dried black raspberries (BRB) or their polyphenolic anthocyanins (AC) have been shown to inhibit the development of N-nitrosomethylbenzylamine (NMBA)-induced esophageal cancer in rats. The present study was conducted to determine if PCA, a major microbial metabolite of BRB AC, also prevents NMBA-induced esophageal cancer in rats. F344 rats were injected with NMBA three times a week for five weeks and then fed control or experimental diets containing 6.1% BRB, an AC-rich fraction derived from BRB, or PCA. Animals were exsanguinated at weeks 15, 25, & 35 to quantify the development of preneoplastic lesions and tumors in the esophagus, and to relate this to the expression of inflammatory biomarkers. At weeks 15 & 25, all experimental diets were equally effective in reducing NMBA-induced esophageal tumorigenesis, as well as in reducing the expression of Pentraxin-3 (PTX3), a cytokine produced by peripheral blood mononuclear cells in response to IL-1β and TNF-α. All experimental diets were also active at reducing tumorigenesis at week 35; however, the BRB diet was significantly more effective than the AC & PCA diets. Further, all experimental diets inhibited inflammation in the esophagus via reducing biomarker (COX-2, iNOS, p-NF-κB, sEH) and cytokine (PTX3) expression. Overall, our data suggest that BRB, their component AC and PCA inhibit NMBA-induced esophageal tumorigenesis, at least in part, by their inhibitory effects on genes associated with inflammation.
    Cancer Prevention Research 03/2014; 7(6). DOI:10.1158/1940-6207.CAPR-14-0003 · 5.27 Impact Factor
  • Cancer Prevention Research 01/2014; 5(11_Supplement):B26-B26. DOI:10.1158/1940-6207.PREV-12-B26 · 5.27 Impact Factor
  • Cancer Prevention Research 01/2014; 5(11_Supplement):A49-A49. DOI:10.1158/1940-6207.PREV-12-A49 · 5.27 Impact Factor
  • Cancer Prevention Research 01/2014; 5(11_Supplement):CN06-01-CN06-01. DOI:10.1158/1940-6207.PREV-12-CN06-01 · 5.27 Impact Factor
  • Stephen S Hecht, Eva Szabo
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    ABSTRACT: The recognition of the link between cigarette smoking and lung cancer in the 1964 Surgeon General's Report initiated definitive and comprehensive research on the identification of carcinogens in tobacco products and the relevant mechanisms of carcinogenesis. The resultant comprehensive data clearly illustrate established pathways of cancer induction involving carcinogen exposure, metabolic activation, DNA adduct formation, and consequent mutation of critical genes along with the exacerbating influences of inflammation, cocarcinogenesis, and tumor promotion. This mechanistic understanding has provided a framework for the regulation of tobacco products and for the development of relevant tobacco carcinogen and toxicant biomarkers that can be applied in cancer prevention. Simultaneously, the recognition of the link between smoking and lung cancer paved the way for two additional critical approaches to cancer prevention that are discussed here: detection of lung cancer at an early, curable stage, and chemoprevention of lung cancer. Recent successes in more precisely identifying at-risk populations and in decreasing lung cancer mortality with helical computed tomography screening are notable, and progress in chemoprevention continues, although challenges with respect to bringing these approaches to the general population exist. Collectively, research performed since the 1964 Report demonstrates unequivocally that the majority of deaths from lung cancer are preventable. Cancer Prev Res; 7(1); 1-8. ©2014 AACR.
    Cancer Prevention Research 01/2014; 7(1):1-8. DOI:10.1158/1940-6207.CAPR-13-0371 · 5.27 Impact Factor
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    ABSTRACT: In 2007, International Agency for Cancer Research presented compelling evidence that linked smokeless tobacco use to the development of human oral cancer. While these findings imply vigorous local carcinogen metabolism, little is known regarding levels and distribution of Phase I, II and drug egress enzymes in human oral mucosa. In the study presented here, we integrated clinical data, imaging and histopathologic analyses of an oral squamous cell carcinoma that arose at the site of smokeless tobacco quid placement in a patient. Immunoblot and immunohistochemical (IHC) analyses were employed to identify tumor and normal human oral mucosal smokeless tobacco-associated metabolic activation and detoxification enzymes. Human oral epithelium contains every known Phase I enzyme associated with nitrosamine oxidative bioactivation with ~2 fold inter-donor differences in protein levels. Previous studies have confirmed ~3.5 fold inter-donor variations in intraepithelial Phase II enzymes. Unlike the superficially located enzymes in non-replicating esophageal surface epithelium, IHC studies confirmed oral mucosal nitrosamine metabolizing enzymes reside in the basilar and suprabasilar region which notably is the site of ongoing keratinocyte DNA replication. Clearly, variations in product composition, nitrosamine metabolism and exposure duration will modulate clinical outcomes. The data presented here form a coherent picture consistent with the abundant experimental data that links tobacco-specific nitrosamines to human oral cancer.
    Cancer Prevention Research 11/2013; 7(1). DOI:10.1158/1940-6207.CAPR-13-0262 · 5.27 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):1502-1502. DOI:10.1158/1538-7445.AM2013-1502 · 9.28 Impact Factor
  • Chemical Research in Toxicology 03/2013; DOI:10.1021/tx400100a · 4.19 Impact Factor
  • Source
    Stephen S Hecht
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    ABSTRACT: Cigarette smoke is a complex mixture of chemicals including multiple genotoxic lung carcinogens. The classic mechanisms of carcinogen metabolic activation to DNA adducts, leading to miscoding and mutations in critical growth control genes, applies to this mixture but some aspects are difficult to establish because of the complexity of the exposure. This article discusses certain features of this mechanism including the role of nicotine and its receptors; lung carcinogens, co-carcinogens and related substances in cigarette smoke; structurally characterized DNA adducts in the lungs of smokers; the mutational consequences of DNA adduct formation in smokers' lungs; and biomarkers of nicotine and carcinogen uptake as related to lung cancer. While there are still uncertainties which may never be fully resolved, the general mechanisms by which cigarette smoking causes lung cancer are well understood and provide insights relevant to prevention of lung cancer, the number one cancer killer in the world, causing 1.37 million deaths per year.
    International Journal of Cancer 12/2012; 131(12):2724-32. DOI:10.1002/ijc.27816 · 5.01 Impact Factor
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    ABSTRACT: Secondhand smoke exposure (SHSe) is a known cause of many adverse health effects in adults and children. Increasingly, SHSe assessment is an element of tobacco control research and implementation worldwide. In spite of decades of development of approaches to assess SHSe, there are still unresolved methodological issues; therefore, a multidisciplinary expert meeting was held to catalogue the approaches to assess SHSe and with the goal of providing a set of uniform methods for future use by investigators and thereby facilitate comparisons of findings across studies. The meeting, held at Johns Hopkins, in Baltimore, Maryland, USA, was supported by the Flight Attendant Medical Research Institute (FAMRI). A series of articles were developed to summarise what is known about self-reported, environmental and biological SHSe measurements. Non-smokers inhale toxicants in SHS, which are mainly products of combustion of organic materials and are not specific to tobacco smoke exposure. Biomarkers specific to SHSe are nicotine and its metabolites (eg, cotinine), and metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Cotinine is the preferred blood, saliva and urine biomarker for SHSe. Cotinine and nicotine can also be measured in hair and toenails. NNAL (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol), a metabolite of NNK, can be determined in the urine of SHS-exposed non-smokers. The selection of a particular biomarker of SHSe and the analytic biological medium depends on the scientific or public health question of interest, study design and setting, subjects, and funding. This manuscript summarises the scientific evidence on the use of biomarkers to measure SHSe, analytical methods, biological matrices and their interpretation.
    Tobacco control 09/2012; 22(3). DOI:10.1136/tobaccocontrol-2011-050298 · 5.15 Impact Factor
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    ABSTRACT: Sphingosine 1-phosphate, a bioactive signaling molecule with diverse cellular functions, is irreversibly degraded by the endoplasmic reticulum enzyme sphingosine 1-phosphate lyase, generating trans-2-hexadecenal and phosphoethanolamine. We recently demonstrated that trans-2-hexadecenal causes cytoskeletal reorganization, detachment, and apoptosis in multiple cell types via a JNK-dependent pathway. These findings and the known chemistry of related α,β-unsaturated aldehydes raise the possibility that trans-2-hexadecenal may interact with additional cellular components. In this study, we show that it reacts readily with deoxyguanosine and DNA to produce the diastereomeric cyclic 1,N(2)-deoxyguanosine adducts 3-(2-deoxy-β-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8R-hydroxy-6R-tridecylpyrimido[1,2-a]purine-10(3H)one and 3-(2-deoxy-β-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8S-hydroxy-6S-tridecylpyrimido[1,2-a]purine-10(3H)one. Thus, our findings suggest that trans-2-hexadecenal produced endogenously by sphingosine 1-phosphate lyase can react directly with DNA forming aldehyde-derived DNA adducts with potentially mutagenic consequences.
    Biochemical and Biophysical Research Communications 06/2012; 424(1):18-21. DOI:10.1016/j.bbrc.2012.06.012 · 2.28 Impact Factor
  • Silvia Balbo, Peter W. Villalta, Stephen S. Hecht
    Cancer Research 06/2012; 72(8 Supplement):4791-4791. DOI:10.1158/1538-7445.AM2012-4791 · 9.28 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):667-667. DOI:10.1158/1538-7445.AM2012-667 · 9.28 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):LB-63-LB-63. DOI:10.1158/1538-7445.AM2012-LB-63 · 9.28 Impact Factor
  • Chemical Research in Toxicology 05/2012; 25(6):1155-6. DOI:10.1021/tx300219b · 4.19 Impact Factor

Publication Stats

15k Citations
2,452.06 Total Impact Points


  • 1998–2015
    • University of Minnesota Duluth
      • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States
  • 1999–2003
    • University of Minnesota Twin Cities
      • Department of Medicine
      Minneapolis, Minnesota, United States
    • Heinrich-Heine-Universität Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1997
    • CUNY Graduate Center
      New York, New York, United States
    • New York Medical College
      New York City, New York, United States
  • 1996
    • The Ohio State University
      • Department of Veterinary Preventive Medicine
      Columbus, OH, United States
    • Vanderbilt University
      • Center in Molecular Toxicology
      Nashville, Michigan, United States
  • 1985–1995
    • University of Chicago
      • Ben May Department for Cancer Research
      Chicago, Illinois, United States
  • 1993
    • Tulane University
      • Department of Chemistry
      New Orleans, LA, United States
  • 1991
    • Medical University of Ohio at Toledo
      Toledo, Ohio, United States
  • 1990
    • National Institute of Environmental Health Sciences
      Durham, North Carolina, United States
  • 1989
    • NCI-Frederick
      Фредерик, Maryland, United States
    • Columbia University
      New York, New York, United States
    • National Cancer Institute (USA)
      • Cancer Etiology Branch (CEB)
      Maryland, United States
  • 1987
    • Umeå University
      Umeå, Västerbotten, Sweden
  • 1984
    • Fox Chase Cancer Center
      Filadelfia, Pennsylvania, United States