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Studies on the mechanism of uroporphyrinogen decarboxylase inhibition in hexachlorobenzene-induced porphyria in the female rat.
- Source :
-
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 1997 Jul; Vol. 145 (1), pp. 23-33. - Publication Year :
- 1997
-
Abstract
- Hexachlorobenzene (HCB)-induced porphyria occurs in female, but not male, rats after a delay of 35 days following HCB treatment. Uroporphyrinogen decarboxylase (UROD) inhibition has been proposed as a primary causative event. To determine whether there also exists a delay phase and a sexual dimorphism for UROD inhibition, groups of male and female rats were given HCB (100 mg/kg/day) from Days 1 to 5. Hepatic uroporphyrin III was markedly increased only after Day 33. Liver cytosol UROD activity in HCB-treated female rats with porphyria at Days 33, 40, 47, 54, and 100 was decreased by over 70% compared to concurrent control, whereas treated male rats as well as nonporphyric female rats had UROD activity comparable to control levels at Days 6, 12, 19, 26, 33, 40, 47, and 54. Level of immunoreactive UROD in cytosol of porphyric rats was not modified by HCB. No gender-related differences in liver cytosol radiolabel level ([14C]HCB given as the fifth dose) were found at Days 6 and 30. Chromatography of liver cytosol showed nonspecific binding of radiolabel to proteins for males, porphyric and nonporphyric females, and loss of UROD activity did not correlate with the amount of radiolabel in the UROD-containing fractions. Thus, the gender-specific decrease in UROD activity observed when porphyria develops in female rats (delay of about 4 weeks), as well as the persistence of low activity and porphyria for months, suggests that UROD inhibition was causally related to porphyria.
- Subjects :
- Analysis of Variance
Animals
Carbon Radioisotopes
Chromatography, Gel
Chromatography, High Pressure Liquid
Cytosol drug effects
Cytosol enzymology
Dialysis
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Female
Fungicides, Industrial administration & dosage
Hexachlorobenzene administration & dosage
Isotope Labeling
Liver enzymology
Liver metabolism
Male
Porphyrias, Hepatic chemically induced
Rats
Rats, Sprague-Dawley
Sex Characteristics
Uroporphyrinogen Decarboxylase blood
Uroporphyrins metabolism
Uroporphyrins urine
Fungicides, Industrial toxicity
Hexachlorobenzene toxicity
Liver drug effects
Porphyrias, Hepatic enzymology
Uroporphyrinogen Decarboxylase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0041-008X
- Volume :
- 145
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Toxicology and applied pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 9221820
- Full Text :
- https://doi.org/10.1006/taap.1997.8157