Experimental
porphyria induced by PHAHs is characterized by a progressive reduction in the activity of UROD. After intoxication with
TCDD, the most porphyrogenic compound known to date, the liver was the principal site of action, as regards both
porphyrin accumulation (mostly uroporphyrin) and the degree of
enzyme impairment; the kidney was the site of the second greatest accumulation; the brain and erythrocytes were unaffected. Additional modifications of the
heme pathway involved induction of the activity of ALAS and, at least in
HCB-induced
porphyria after
iron pretreatment, may have involved reduced activity of
uroporphyrinogen III cosynthetase. These changes can alter the amount and the isomeric composition of
uroporphyrinogens and
uroporphyrins present in the liver in a way that is likely to help reduce formation of
coproporphyrinogen III in porphyric animals. As in the human syndrome
porphyria cutanea tarda,
iron administration increased
porphyrin accumulation and the degree of reduction of UROD activity in mice fed
HCB. Mice fed
HCB also presented an activation of the type O form of XO. This activation was independent of tissue injury derived from the lipid peroxidation that was concomitant with
iron administration. The increase in activity of the type O form of XO may be a characteristic feature of the liver damage found in PHAH intoxication and, in intoxicated animals, could be a source in the liver of
oxidant species involved in the mechanism of UROD inactivation--if this inactivation is in fact due to an oxidative reaction.