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.