STUDIES ON THE MECHANISM OF UROPORPHYRINOGEN DECARBOXYLASE INHIBITIONIN HEXACHLOROBENZENE-INDUCED PORPHYRIA IN THE FEMALE RAT

Hexachlorobenzene (HCB)-induced porphyria occurs in female, but not ma le, rats after a delay of 35 days following HCB treatment. Uroporphyri nogen decarboxylase (UROD) inhibition has been proposed as a primary c ausative event. To determine whether there also exists a delay phase a nd 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 uroporph yrin 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 URO D 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 cytos ol radiolabel level ([C-14]HCB given as the fifth dose) were found at Days 6 and 30. Chromatography of liver cytosol showed nonspecific bind ing of radiolabel to proteins for males, porphyric and nonporphyric fe males, 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 activ ity and porphyria for months, suggests that UROD inhibition was causal ly related to porphyria. (C) 1997 Academic Press.