Y. Frater et al., FORMATION OF N-METHYL PROTOPORPHYRIN IN CHEMICALLY-INDUCED PROTOPORPHYRIA - STUDIES WITH A NOVEL PORPHYROGENIC AGENT, Archives of toxicology, 67(3), 1993, pp. 179-185
,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.