Formation of N-methyl protoporphyrin in chemically-induced protoporphyria. Studies with a novel porphyrogenic agent.
1-[4-(3-Acetyl-2,4,6-trimethylphenyl)-2,6-cyclohexanedionyl]-O-eth yl propionaldehyde oxime (for short ATMP) is a novel porphyrogenic agent causing hepatic protoporphyria in the mouse. Mice given a single dose of the drug showed 24 h later a 70% inhibition of liver ferrochelatase and marked accumulation of protoporphyrin. These changes were not seen in similarly treated rats, guinea pigs, hamsters or chick embryos. A green pigment was isolated from the liver of mice treated with ATMP and identified by its electronic absorption spectrum and chromatographic properties on HPLC as N-methyl protoporphyrin. The ATMP pigment markedly inhibited the enzyme ferrochelatase in vitro, thus supporting its identification as N-methyl protoporphyrin. Two inhibitors of liver cytochrome P450, compound SKF 525-A and piperonyl butoxide, when given before ATMP, afforded protection against ATMP-induced porphyria and production of N-methyl protoporphyrin, suggesting a role of cytochrome P450 in the induction of the metabolic disorder. The most likely interpretation for these findings is therefore that ATMP is metabolized in the mouse to a reactive species, which in turn alkylates the haem moiety of liver cytochrome P450, thus producing N-methyl protoporphyrin. This inhibits ferrochelatase and, as a secondary response, protoporphyrin accumulates. This pathway of metabolism to the postulated reactive metabolite presumably does not occur to a significant extent in the other species examined and hence is the likely basis for the species difference in protoporphyria.
Medical Research Council Toxicology Unit, Carshalton, Surrey, UK.
Y
Y
Frater
A
A
Brady
E A
EA
Lock
F
F
De Matteis
D000818:Animals; D006224:Cricetinae; D003512:Cyclohexanones / Q000494:pharmacology* / Q000633:toxicity; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D005294:Ferrochelatase / Q000187:drug effects; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology* / Q000633:toxicity; D017094:Porphyrias, Hepatic / Q000139:chemically induced* / Q000378:metabolism; D011166:Porphyrins / Q000096:biosynthesis / Q000302:isolation & purification; D011524:Protoporphyrins / Q000096:biosynthesis* / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D003512:Cyclohexanones; D065607:Cytochrome P-450 Enzyme Inhibitors; D010091:Oximes; D011166:Porphyrins; D011524:Protoporphyrins; C081243:1-(4-(3-acetyl-2,4,6-trimethylphenyl)-2,6-cyclohexanedionyl)-O-ethyl propionaldehyde oxime; C028842:N-methylprotoporphyrin IX; D003577:Cytochrome P-450 Enzyme System; D005294:Ferrochelatase