FORMATION OF N-METHYL PROTOPORPHYRIN IN CHEMICALLY-INDUCED PROTOPORPHYRIA - STUDIES WITH A NOVEL PORPHYROGENIC AGENT

,6-trimethylphenyl)-2,6-cyclohexanedionyl]-O-ethyl propionaldehyde oxi me (for short ATMP) is a novel porphyrogenic agent causing hepatic pro toporphyria in the mouse. Mice given a single dose of the drug showed 24 h later a 70% inhibition of liver ferrochelatase and marked accumul ation of protoporphyrin. These changes were not seen in similarly trea ted rats, guinea pigs, hamsters or chick embryos. A green pigment was isolated from the liver of mice treated with ATMP and identified by it s electronic absorption spectrum and chromatographic properties on HPL C 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, comp ound SKF 525-A and piperonyl butoxide, when given before ATMP, afforde d 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 f indings is therefore that ATMP is metabolized in the mouse to a reacti ve species, which in tum alkylates the haem moiety of liver cytochrome P450, thus producing N-methyl protoporphyrin. This inhibits ferrochel atase and, as a secondary response, protoporphyrin accumulates. This p athway of metabolism to the postulated reactive metabolite presumably does not occur to a significant extent in the other species examined a nd hence is the likely basis for the species difference in protoporphy ria.