EFFECT OF THE PROTOPORPHYRINOGEN OXIDASE-INHIBITING HERBICIDE FOMESAFEN ON LIVER UROPORPHYRIN AND HEPTACARBOXYLIC PORPHYRIN IN 2 MOUSE STRAINS

The effect of the protoporphyrinogen oxidase-inhibiting herbicide fome safen on liver porphyrin accumulation was studied in long-term high-do se experiments. Fomesafen caused liver accumulation of uroporphyrin an d heptacarboxylic porphyrin when fed at 0.25% in the diet to male ICR mice for 5 months (fomesafen-treated mice: 52 nmol uroporphyrin, 21 nm ol heptacarboxylic porphyrin/g liver; control mice: traces of uroporph yrin, heptacarboxylic porphyrin not detected). Uroporphyrinogen decarb oxylase activity was depressed to about 25% of control values. Iron tr eatment accelerated the development of this porphyria cutanea tarda-li ke experimental porphyria both in ICR and C57B1/6J mice. In contrast t o other uroporphyrinogen decarboxylase inhibitors, fomesafen treatment did not increase the cytochrome P450IA-related activities and the amo unt of P450IA2 protein was shown to be significantly decreased by West ern immunoblotting. Thus, fomesafen is a unique chemical that inhibits both the oxidation of protoporphyrinogen as well as the conversion of uroporphyrinogen to coproporphyrinogen. However, the accumulation of highly carboxylated porphyrins is evident only after prolonged treatme nt with high doses of the herbicide.