Experimental hepatic uroporphyria induced by the diphenyl-ether herbicide fomesafen in male DBA/2 mice.
Hepatic uroporphyria can be readily induced by a variety of treatments in mice of the C57BL strains, whereas DBA/2 mice are almost completely resistant. However, feeding of the protoporphyrinogen oxidase-inhibiting herbicide fomesafen (0.25% in the diet for 18 weeks) induced hepatic uroporphyria in male DBA/2N mice (liver porphyrin content up to 150 nmol/g, control animals 1 nmol/g), whereas fomesafen-treated male C57BL/6N mice displayed only a slight elevation of liver porphyrins (approximately 5 nmol/g). The profile of accumulated hepatic porphyrins in fomesafen-treated DBA/2N mice resembled the well-characterised uroporphyria induced by polyhalogenated aromatic hydrocarbons, while histological examination confirmed the presence of uroporphyria-specific cytoplasmic inclusions in the hepatocytes. Uroporphyrinogen decarboxylase activity decreased to about 30% of control values in fomesafen-treated DBA/2N mice; microsomal methoxyresorufin O-dealkylase activity was slightly reduced. The amount of CYP1A1 and CYP1A2 mRNA, as determined by real-time PCR, was not significantly changed; mRNA encoding the housekeeping 5-aminolevulinic acid synthase was elevated 10-fold. Total liver iron was slightly increased. A similar uroporphyria was induced by the herbicide formulation Blazer, containing a structurally related herbicide acifluorfen, when fed to DBA/2N mice at a dose corresponding to 0.25% of acifluorfen in the diet. Since DBA/2 mice are almost completely resistant to all well-characterised porphyrogenic chemicals, the results suggest the possible existence of a yet unknown mechanism of uroporphyria induction, to which the DBA/2 mouse strain is more sensitive than the C57BL strain.
Krijt
Jan
J
Institute of Pathophysiology, 1st Medical Faculty, Charles University, 128 53, Prague, Czech Republic. jkri@lfl.cuni.cz <jkri@lfl.cuni.cz>
Psenák
Oskar
O
Vokurka
Martin
M
Chlumská
Alena
A
Fakan
Frantisek
F
D000818:Animals; D001549:Benzamides / Q000633:toxicity*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006540:Herbicides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010647:Phenyl Ethers / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D017094:Porphyrias, Hepatic / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D013045:Species Specificity; D014578:Uroporphyrins / Q000032:analysis / Q000096:biosynthesis*
D001549:Benzamides; D006540:Herbicides; D010647:Phenyl Ethers; D012333:RNA, Messenger; D014578:Uroporphyrins; C031538:phenyl ether; D019388:Cytochrome P-450 CYP1A2; C088563:fomesafen