Effect of the protoporphyrinogen oxidase-inhibiting herbicide fomesafen on liver uroporphyrin and heptacarboxylic porphyrin in two mouse strains.
The effect of the protoporphyrinogen oxidase-inhibiting herbicide fomesafen on liver porphyrin accumulation was studied in long-term high-dose experiments. Fomesafen caused liver accumulation of uroporphyrin and heptacarboxylic porphyrin when fed at 0.25% in the diet to male ICR mice for 5 months (fomesafen-treated mice: 52 nmol uroporphyrin, 21 nmol heptacarboxylic porphyrin/g liver; control mice: traces of uroporphyrin, heptacarboxylic porphyrin not detected). Uroporphyrinogen decarboxylase activity was depressed to about 25% of control values. Iron treatment accelerated the development of this porphyria cutanea tarda-like experimental porphyria both in ICR and C57B1/6J mice. In contrast to other uroporphyrinogen decarboxylase inhibitors, fomesafen treatment did not increase the cytochrome P450IA-related activities and the amount of P450IA2 protein was shown to be significantly decreased by Western 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 treatment with high doses of the herbicide.
Krijt
J
J
Department of Pathological Physiology, First Medical Faculty, Charles University, Prague, Czech Republic.
Vokurka
M
M
Sanitrak
J
J
Janousek
V
V
van Holsteijn
I
I
Blaauboer
B J
BJ
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D005420:Flavoproteins; D055768:Halogenated Diphenyl Ethers; D006540:Herbicides / Q000494:pharmacology*; D007668:Kidney / Q000737:chemistry / Q000187:drug effects; D008099:Liver / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D024101:Mitochondrial Proteins; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010647:Phenyl Ethers / Q000494:pharmacology; D011166:Porphyrins / Q000737:chemistry*; D050768:Protoporphyrinogen Oxidase; D014578:Uroporphyrins / Q000737:chemistry*
D001549:Benzamides; D005420:Flavoproteins; D055768:Halogenated Diphenyl Ethers; D006540:Herbicides; D024101:Mitochondrial Proteins; D010647:Phenyl Ethers; D011166:Porphyrins; D014578:Uroporphyrins; C042771:heptacarboxylic porphyrin; C016027:oxyfluorofen; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C493979:Ppox protein, mouse; D050768:Protoporphyrinogen Oxidase; C088563:fomesafen