Document Detail

Dihydroxy-, hydroxyspirolactone-, and dihydroxyspirolactone-urochlorins induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the liver of mice.
MedLine Citation:
PMID:  17173380     Owner:  NLM     Status:  MEDLINE    
Previous work has shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes porphyria, enhanced by iron, in C57BL/6J mice with marked accumulation in the liver of uroporphyrin I and III isomers and heptacarboxylic acid III and is one model of human porphyria cutanea tarda. Preliminary examination by HPLC also indicated the presence of some oxygenated side chain uroporphyrin derivatives. Here, the porphyrin constituents of TCDD-induced porphyric liver have been examined by HPLC/electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC/ESI-Q-TOFMS) to characterize the major and minor porphyrins present in hepatic tissue. As well as the major constituents uroporphyrins I and III, we identified the isomers of heptacarboxylic, hexacarboxylic, and pentacarboxylic acid porphyrins arising from intermediates in the stepwise decarboxylation of uroporphyrinogen I and III to coproporphyrinogens. In addition, monohydroxy analogues of uroporphyrin isomers were detected hydroxylated in the acetic acid and beta-positions of propionic acid side chains and in the meso ring position. Of particular note, for the first time for human and experimental porphyrias, we found chlorins (dihydroxy-, hydroxyspirolactone- ,and dihydroxyspirolactone-urochlorins) consistent with those derived from an epoxyurochlorin structure, formed by oxidation of the double bond of a pyrrole ring of uroporphyrinogen I and III isomers. The findings demonstrate that oxygen insertion into the pyrrole rings of uroporphyrinogens occurs under pathological circumstances in vivo and support the evidence for an oxidative cellular environment present in TCDD-treated porphyric tissue.
Chang-Kee Lim; Malcolm Danton; Bruce Clothier; Andrew G Smith
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Chemical research in toxicology     Volume:  19     ISSN:  0893-228X     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2006 Dec 
Date Detail:
Created Date:  2006-12-18     Completed Date:  2007-03-09     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1660-7     Citation Subset:  IM    
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MeSH Terms
Chromatography, High Pressure Liquid
Liver / drug effects*,  metabolism
Mice, Inbred C57BL
Molecular Structure
Spectrometry, Mass, Electrospray Ionization
Spironolactone / metabolism*
Tandem Mass Spectrometry
Tetrachlorodibenzodioxin / toxicity*
Uroporphyrinogens / metabolism*
Uroporphyrins / metabolism*
Grant Support
G0001263//Medical Research Council
Reg. No./Substance:
0/Uroporphyrinogens; 0/Uroporphyrins; 27O7W4T232/Spironolactone; DO80M48B6O/Tetrachlorodibenzodioxin

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