Document Detail

Metabolism of aromatic and heterocyclic amine bladder carcinogens: bioanalytical considerations.
MedLine Citation:
PMID:  2128813     Owner:  NLM     Status:  MEDLINE    
Aromatic and heterocyclic amines are environmental chemicals which can cause bladder cancer in man. Because these chemicals cause carcinomas at a site distal to their portals of entry, metabolic processes are involved in initiation of their carcinogenic effects. N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) and its deformylated analogue, ANFT, were used as model compounds to assess metabolism. Electrochemical properties of ANFT made liquid chromatography with electrochemical detection a specific and sensitive method for analysis. Peroxidatic metabolism of ANFT by prostaglandin H synthase (PHS) in the presence of N-acetylcysteine resulted in the formation of 2-amino-4-(5-nitro-2-furyl)-5-(N-acetylcystein-S-yl)thiazole (ANFT-MA). This thioether product has an oxidation potential significantly lower than ANFT. Rat urinary excretion of ANFT-MA was significantly decreased with peroxidase inhibitors, 6-n-propyl-2-thiouracil and methimazole. Inhibitors did not alter excretion of ANFT or prostaglandin E2, a PHS product of arachidonic acid metabolism. 1H and 13C-NMR were selected to explore potential structural differences between ANFT and FANFT which might explain preferential PHS metabolism of ANFT. Evidence for a "zwitterion" configuration for ANFT but not FANFT was observed. ANFT in the "zwitterion" configuration would be a better reducing co-substrate. Chemical synthesis and GC-MS fragmentation patterns identified 3-(2,3-dihydro-1-methyl-2-pyrrolyl)pyridine as a peroxidatic product of nicotine metabolism. This peroxidatic product was found in urine from a cigarette smoker in an amount approximately 6% that observed for continine. Thus, a potential rôle for peroxidative metabolism was demonstrated in man.
M B Mattammal; V M Lakshmi; T V Zenser; B B Davis
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.; Review    
Journal Detail:
Title:  Journal of pharmaceutical and biomedical analysis     Volume:  8     ISSN:  0731-7085     ISO Abbreviation:  J Pharm Biomed Anal     Publication Date:  1990  
Date Detail:
Created Date:  1991-07-03     Completed Date:  1991-07-03     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8309336     Medline TA:  J Pharm Biomed Anal     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  151-8     Citation Subset:  IM    
Geriatric Research, Education and Clinical Center, Veterans Administration Medical Center, St. Louis, MO 63125.
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MeSH Terms
Carcinogens / metabolism*
Chromatography, High Pressure Liquid
FANFT / analogs & derivatives*,  metabolism*
Prostaglandin-Endoperoxide Synthases / pharmacology
Urinary Bladder Neoplasms / chemically induced*
Grant Support
Reg. No./Substance:
0/Carcinogens; 24554-26-5/FANFT; 38514-71-5/ANFT; EC Synthases

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