Abstract:
:The procarcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine formed during the cooking of foods. Metabolism of PhIP by CYP1A2 differs substantially between humans and rodents, with more N2-hydroxylation (activation) and less 4'-hydroxylation (detoxication) in humans. Therefore, the human response to PhIP and other heterocyclic amine exposure may not be accurately reflected in the laboratory rodent. By generating mouse models expressing the human genes, species differences in heterocyclic amine metabolism can be addressed. Two transgenic mouse lines were developed, one expressing the human CYP1A1 CYP1A2 transgene in a mouse Cyp1a1-null background (hCYP1A1) and another expressing human CYP1A1 CYP1A2 in a mouse Cyp1a2-null background (hCYP1A2). Expression of human CYP1A2 protein was detected in the liver and also at considerably lower levels in extrahepatic tissues such as lung, kidney, colon, and heart. In the hCYP1A1 and hCYP1A2 mice, 3-methylcholanthrene (3-MC) induced both human CYP1A1 and CYP1A2 protein in the liver. Differences in the metabolism of the heterocyclic amine PhIP were observed between wild-type and hCYP1A2 mice. PhIP was preferentially metabolized by N2-hydroxylation in hCYP1A2 mice, whereas in wild-type mice, 4'-hydroxylation was the predominant pathway. Since the N2-hydroxylation pathway for PhIP metabolism has been reported to be predominant in humans, these results illustrate the potential effectiveness of using these transgenic, humanized mice as models for determining human health risks to PhIP and other heterocyclic amines instead of wild-type mice.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Cheung C,Ma X,Krausz KW,Kimura S,Feigenbaum L,Dalton TP,Nebert DW,Idle JR,Gonzalez FJdoi
10.1021/tx050136gsubject
Has Abstractpub_date
2005-09-01 00:00:00pages
1471-8issue
9eissn
0893-228Xissn
1520-5010journal_volume
18pub_type
杂志文章abstract::Guidance from the Food and Drug Administration on drug interaction studies does not include a specific section on contributions of metabolites to observed inhibitory drug-drug interactions, and the quantitative role of drug metabolites in inhibitory drug-drug interactions is not presently known. The current work was u...
journal_title:Chemical research in toxicology
pub_type: 杂志文章,评审
doi:10.1021/tx800491e
更新日期:2009-02-01 00:00:00
abstract::To prevent the accumulation of reactive oxygen species and limit associated damage to biological macromolecules, cells express a variety of oxidant-detoxifying enzymes, including peroxiredoxins. In Saccharomyces cerevisiae, the peroxiredoxin Tsa1 plays a key role in peroxide clearance and maintenance of genome stabili...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.8b00346
更新日期:2019-03-18 00:00:00
abstract::O6-Benzyl-2'-deoxyguanosine is a potential antitumor drug modulator that is intended to reduce or eliminate O6-alkylguanine-DNA alkyltransferase activity in tumors prior to treatment with genotoxic chemotherapeutic alkylating agents. The rationale for using this compound instead of the more active O6-benzylguanine and...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00042a008
更新日期:1994-11-01 00:00:00
abstract::In a recent study, we reported that interleukin (IL)-4 had a protective role against acetaminophen (APAP)-induced liver injury (AILI), although the mechanism of protection was unclear. Here, we carried out more detailed investigations and have shown that one way IL-4 may control the severity of AILI is by regulating g...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx2003992
更新日期:2012-01-13 00:00:00
abstract::Coumadin (R/S-warfarin) anticoagulant therapy poses a risk to over 50 million Americans, in part due to interpersonal variation in drug metabolism. Consequently, it is important to understand how metabolic capacity is influenced among patients. Cytochrome P450s (P450 or CYP for a specific isoform) catalyze the first m...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx1000283
更新日期:2010-05-17 00:00:00
abstract::We propose here a combined gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) metabolic profiling strategy to elucidate the toxicity in rats induced by orally administered multiglycosides of Tripterygium wilfordii Hook. f. (GTW) in multiple organs including the kidney, liv...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx7002905
更新日期:2008-02-01 00:00:00
abstract::Anxiolytic kava products have been associated with rare but severe hepatotoxicity in humans. This adverse potential has never been captured in animal models, and the responsible compound(s) remains to be determined. The lack of such knowledge greatly hinders the preparation of a safer kava product and limits its benef...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx5003194
更新日期:2014-10-20 00:00:00
abstract::The process of disinfecting drinking water inadvertently leads to the formation of numerous disinfection byproducts (DBPs). Some of these are mutagenic, genotoxic, teratogenic, and cytotoxic, as well as potentially carcinogenic both in vivo and in vitro. We investigated the in vitro biological activity of five DBPs: t...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.5b00283
更新日期:2015-10-19 00:00:00
abstract::1,N6-ethenoadenine (εA) is a mutagenic lesion and biomarker observed in numerous cancerous tissues. Two pathways are responsible for its repair: base excision repair (BER) and direct reversal repair (DRR). Alkyladenine DNA glycosylase (AAG) is the primary enzyme that excises εA in BER, generating stable intermediates ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.0c00089
更新日期:2020-07-20 00:00:00
abstract::Nitroaromatic compounds represent a major class of industrial chemicals that are also found in nature. Polycyclic derivatives are regarded as potent mutagens and carcinogens following bioactivation to produce nitrenium electrophiles that covalently modify DNA to afford N-linked C8-2'-deoxyguanosine (C8-dG) lesions tha...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00411
更新日期:2020-02-17 00:00:00
abstract::Zileuton, an inhibitor of 5-lipooxygenase, the initial enzyme in the leukotriene pathway, was marketed as a new treatment for asthma. This drug has been associated with liver toxicity, which has limited its clinical usefulness. We provide evidence here that the liver toxicity likely involves a sequence of biotransform...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0341409
更新日期:2004-02-01 00:00:00
abstract::The gender differences in the in vitro microsomal metabolic activation of hepatotoxic clivorine, a representative naturally occurring hepatotoxic otonecine type pyrrolizidine alkaloid, in Sprague-Dawley rats and their relation to the gender differences in susceptibility to clivorine intoxication were reported in the p...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0340302
更新日期:2003-06-01 00:00:00
abstract::2'-Deoxyoxanosine (dOxo) is a novel DNA lesion produced from dGuo by reaction with nitrous acid or nitric oxide [Suzuki, T., Yamaoka, R., Nishi, M., Ide, H., and Makino, K. (1996) J. Am. Chem. Soc. 118, 2515-2516]. We investigated the reaction of dOxo with glycine (Gly) under physiological conditions. When 5 mM dOxo w...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx990164x
更新日期:2000-04-01 00:00:00
abstract::Quantitation of DNA adducts could provide critical information on the relationship between exposure to tobacco smoke and cancer risk in smokers. In this study, we developed a robust and sensitive liquid chromatography-tandem mass spectrometry method for the analysis of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasin...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx300282k
更新日期:2013-01-18 00:00:00
abstract::Flavonols are potent naturally occurring antioxidants. Chemical oxidation reactions in combination with modern spectroscopic techniques have been employed to identify oxidized flavonoid products. Although many oxidized derivatives have been generated from commercially available starting materials, few studies have dev...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx034242z
更新日期:2004-06-01 00:00:00
abstract::( E)-4-Hydroxynon-2-enal (HNE), an electrophilic bifunctional cytotoxic lipid peroxidation product, forms covalent adducts with nucleophilic side chains of amino acid residues. HNE-derived adducts have been implicated in many pathophysiological processes including atherosclerosis, diabetes, and Alzheimer's disease. Tr...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx8000303
更新日期:2008-07-01 00:00:00
abstract::Hemoglobin adducts have been used to assess exposure to carcinogenic compounds in tobacco smoke. However, because of background levels in nonsmokers, most adducts that have been studied are not useful for monitoring low-level exposure. Bergmark [(1997) Chem. Res. Toxicol. 10, 78-84] showed that the level of adducts of...
journal_title:Chemical research in toxicology
pub_type: 临床试验,杂志文章
doi:10.1021/tx9900728
更新日期:1999-10-01 00:00:00
abstract::Bisphenol A (BPA) is used in the production of polycarbonate plastics and epoxy resins for baby bottles, liners of canned food, and many other consumer products. Previously, BPA has been shown to reduce the activity of several antioxidant enzymes, which may contribute to oxidative stress. However, the underlying mecha...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx400036v
更新日期:2013-03-18 00:00:00
abstract::A series of tether-linked bis netropsins have been synthesized in order to assess the phasing problem, which arises because of the lack of dimensional correspondence between oligopeptides and oligonucleotides in DNA binding characteristics. The consequences of incorporating variable-length flexible and rigid tethers [...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00014a013
更新日期:1990-03-01 00:00:00
abstract::Metabolic bioactivation, glutathione depletion, and covalent binding are the early hallmark events after acetaminophen (APAP) overdose. However, the subsequent metabolic consequences contributing to APAP-induced hepatic necrosis and apoptosis have not been fully elucidated. In this study, serum metabolomes of control ...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx800464q
更新日期:2009-04-01 00:00:00
abstract::A newly developed recombinant yeast strain, in which the human estrogen receptor has been stably integrated into the genome of the yeast, was used to gain information on the estrogenic activity of a large series of dietary flavonoids. Among 23 flavonoids investigated, 8 were found to markedly stimulate the transcripti...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx970170y
更新日期:1998-06-01 00:00:00
abstract::Mouse cytochrome P450 2A5 (CYP2A5) is upregulated in various pathophysiological liver diseases and induced by structurally variable hepatotoxic chemicals. A putative common feature for all of these conditions is altered cellular redox status. Nuclear factor erythroid 2-like 2 (Nrf2) is a transcription factor that is p...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx100084c
更新日期:2010-05-17 00:00:00
abstract::Estrogen exposure through early menarche, late menopause, and hormone replacement therapy increases the risk factor for hormone-dependent cancers. Although the molecular mechanisms are not completely established, DNA damage by quinone electrophilic reactive intermediates, derived from estrogen oxidative metabolism, is...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx8000797
更新日期:2008-07-01 00:00:00
abstract::The microsomal metabolism of the carcinogen N-nitrosodimethylamine (NDMA) was suggested to be initiated by hydrogen atom abstraction to form an alpha-nitrosamino radical, which either oxidizes further to an alpha-hydroxy nitrosamine as the initial product of the activating dealkylation pathway or fragments to the nitr...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00010a006
更新日期:1989-07-01 00:00:00
abstract::The pharmacodynamics of rat hepatic cytochrome P450 2B (P450 2B) induction by phenobarbital (PB) and two structural congeners, dl-5-ethyl-5-phenylhydantoin (EPH) and dl-5-ethyl-5-phenyloxazolidinedione (EPO), were investigated. The in vivo induction of P450 2B was probed in F344/NCr rats by measuring immunoreactive he...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx00032a008
更新日期:1993-03-01 00:00:00
abstract::Exposure to the tobacco-related nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine is carcinogenic to humans. Metabolic activation of NNK leads to the formation of DNA adducts, which play a critical role in NNK carcinogenesis. Adducts specific to NNK result from covalent linkag...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx050028u
更新日期:2005-06-01 00:00:00
abstract::Reactive nitrogen species (RNS) are produced during infection and inflammation, and the effects of these agents on proteins, DNA, and lipids are well recognized. In contrast, the effects of RNS damaged metabolites are less appreciated. 5-Amino-3-β-(d-ribofuranosyl)-3 H-imidazo-[4,5- d][1,3]oxazine-7-one (oxanosine) an...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.8b00342
更新日期:2019-03-18 00:00:00
abstract::Recent reports by Galeazzi and co-workers demonstrated the susceptibility of Abeta(1-42) to undergo dityrosine formation via peroxidase-catalyzed tyrosine cross-linking. We have formed dityrosine cross-links in Abeta(1-40) using these enzymatic conditions as well as a copper-H(2)O(2) method. The efficiency of dityrosi...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx025666g
更新日期:2003-04-01 00:00:00
abstract::The importance of adsorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis is expected to grow substantially due to recent failures in detecting severe toxicity issues of new chemical entities during preclinical/clinical development. Traditionally, safety risk assessment studies for humans have b...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/acs.chemrestox.9b00364
更新日期:2020-01-21 00:00:00
abstract::Organochlorine (OC) compounds are some of the main toxicants present in the food web and target several cellular systems including the nonspecific immune system. The objective of this study was to test the hypothesis that OC compounds that activate neutrophils share common structural features. Using activation of phos...
journal_title:Chemical research in toxicology
pub_type: 杂志文章
doi:10.1021/tx0155449
更新日期:2002-02-01 00:00:00