Dihydroxy-, hydroxyspirolactone-, and dihydroxyspirolactone-urochlorins induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the liver of mice.

Abstract

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.

• Authors: Chang-Kee Lim, Malcolm Danton, Bruce Clothier, Andrew G Smith
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 19 Issue 12 Pg. 1660-7 (Dec 2006) ISSN: 0893-228X [Print] United States
• PMID: 17173380 (Publication Type: Journal Article)

Chemical References

• Polychlorinated Dibenzodioxins
• Uroporphyrinogens
• Uroporphyrins
• Spironolactone

Topics

• Animals
• Chromatography, High Pressure Liquid
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Structure
• Oxidation-Reduction
• Polychlorinated Dibenzodioxins (toxicity)
• Spectrometry, Mass, Electrospray Ionization
• Spironolactone (metabolism)
• Tandem Mass Spectrometry
• Uroporphyrinogens (metabolism)
• Uroporphyrins (metabolism)