Effects of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethylphenyl) cyclohex-2-enone on hepatic haem biosynthesis: species differences in hepatic porphyria.
2-[1-(Ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethylphenyl) cyclohex-2-enone (ETC) is a novel alkyl ketone herbicide. Continuous administration of ETC to mice for 28 days resulted in marked liver enlargement and severe intrahepatic cholestasis. These effects have been shown to result directly from a rapid and marked accumulation of porphyrin in the liver. The porphyrin which accumulates in the liver has been identified as protoporphyrin IX and dose response and time course studies confirm prior inhibition of mitochondrial ferrochelatase as the causal lesion. ETC was a very potent porphyrinogenic compound in mice, with a no-effect level for a single oral dose of 1 mg/kg. Rats and hamsters were insensitive to this type of hepatotoxicity following single oral doses of up to 750 mg/kg or following repeated, and indeed prolonged administration. The sensitivity of different species to ETC-induced porphyria correlated with the effect of ETC on hepatic ferrochelatase activity. The inhibition of ferrochelatase activity and the hepatic porphyria in mice were both found to be readily reversible upon withdrawal of ETC.
Brady
A M
AM
Toxicology Section, Investigative Zeneca PLC, Macclesfield, Cheshire, UK.
Hasmall
R L
RL
Elcombe
B M
BM
Lock
E A
EA
De Matteis
F
F
D000284:Administration, Oral; D000818:Animals; D006224:Cricetinae; D003512:Cyclohexanones / Q000633:toxicity*; D005260:Female; D005294:Ferrochelatase / Q000378:metabolism; D006418:Heme / Q000096:biosynthesis*; D006540:Herbicides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D051379:Mice; D017094:Porphyrias, Hepatic / Q000139:chemically induced / Q000378:metabolism*; D011166:Porphyrins / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D003512:Cyclohexanones; D006540:Herbicides; D011166:Porphyrins; D006418:Heme; C084988:2-(1-(ethoxyimino)propyl)-3-hydroxy-5-(2,4,6-trimethylphenyl)cyclohex-2-enone; D005294:Ferrochelatase