Herbicide-induced experimental variegate porphyria in mice: tissue porphyrinogen accumulation and response to porphyrogenic drugs.
Administration of oxadiazon or oxyfluorfen (1000 ppm in the diet) to male BALB/c mice for 9 days resulted in experimental porphyria, resembling the acute phase of human variegate porphyria. Urinary concentrations of 5-aminolevulinic acid and porphobilinogen reached 1500 and 3000 mumol/L, respectively. Both herbicides caused a decrease of protoporphyrinogen oxidase activity in liver and kidney. Brain protoporphyrinogen oxidase activity was not altered. Liver and kidney porphyrin content increased to 11 and 17 nmol/g, respectively (control mice, 2 nmol/g). Over 50% of liver and kidney porphyrins were in the reduced (porphyrinogen) form. Bile of oxadiazon-treated mice contained 700 nmol/mL of protoporphyrinogen (control mice, 15 nmol/mL). Porphyrin content of the trigeminal nerve increased from 1 nmol/g in control animals to 11 nmol/g in oxadiazon-treated animals, suggesting a possible contribution of peripheral nerve porphyrins to porphyric neuropathy. Mice treated with 125 ppm of oxadiazon in the diet for 9 days excreted moderately elevated levels of porphobilinogen in urine (control mice, less than 50 mumol/L; treated mice, 330 mumol/L). Administration of phenobarbital or phenytoin (single injections on days 7, 8, and 9) increased the urinary porphobilinogen concentration to 3500 mumol/L. This response to porphyrogenic drugs resembles the response observed in human acute porphyrias.
Krijt
J
J
Institute of Pathophysiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Stranska
P
P
Maruna
P
P
Vokurka
M
M
Sanitrak
J
J
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D055768:Halogenated Diphenyl Ethers; D006540:Herbicides / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010069:Oxadiazoles / Q000633:toxicity; D010647:Phenyl Ethers / Q000494:pharmacology; D011162:Porphobilinogen / Q000652:urine; D011164:Porphyrias / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011165:Porphyrinogens / Q000378:metabolism*; D011166:Porphyrins / Q000652:urine
D055768:Halogenated Diphenyl Ethers; D006540:Herbicides; D010069:Oxadiazoles; D010647:Phenyl Ethers; D011165:Porphyrinogens; D011166:Porphyrins; C016027:oxyfluorofen; D011162:Porphobilinogen; D003577:Cytochrome P-450 Enzyme System; C012466:oxadiazon