1. A hepatic green pigment with inhibitory properties towards the enzyme ferrochelatase has been isolated from the liver of mice treated with griseofulvin and identified as N-methylprotoporphyrin. 2. All four structural isomers of N-methylprotoporphyrin have been demonstrated to be present, NA, where ring A of protoporphyrin IX is N-methylated, being the predominant isomer. 3. In addition to N-methylprotoporphyrin, a second green pigment, present in far greater amounts, was also isolated from the liver of griseofulvin-treated mice. This second green pigment is also an N-monosubstituted protoporphyrin, but in this case the substituent on the pyrrole nitrogen atom appears to be intact griseofulvin rather than a methyl group. 4. The fragmentation of this adduct in tandem m.s. studies suggests that griseofulvin is bound to the pyrrole nitrogen through one of its carbon atoms and further suggests that N-methylprotoporphyrin may arise as a secondary product from the major griseofulvin pigment.
A hepatic green pigment, inhibitory toward ferrochelatase, has been isolated from the liver of mice treated with griseofulvin, isogriseofulvin, or 3,5-diethoxycarbonyl-1,4-dihydrocollidine and has been shown to exhibit identical chromatographic characteristics to authentic N-methyl protoporphyrin. All four possible structural isomers have been demonstrated, and each drug produced primarily the same isomer. N-Methyl protoporphyrin has also been found in very small amounts in the liver of untreated mice, but the isomeric composition appeared to differ from that of the drug-induced N-methyl protoporphyrin. Intraperitoneal administration of 3,5-diethoxy-carbonyl-1,4-dihydrocollidine to female C3H/He/Ola and NIH/Ola inbred mice produced a marked dose-related loss of hepatic ferrochelatase activity, which was identical in magnitude in the two strains. Induction of hepatic 5-aminolevulinate synthase (ALA-S), and accumulation of liver protoporphyrin, however, were greater in C3H/He/Ola mice. The strain difference in ALA-S response was most marked when inhibition of ferrochelatase (the "specific" effect of the drug) was maximal, and this suggests that a genetic variation exists in the sensitivity of ALA-S to a second drug action, the so-called nonspecific action, which is shared by many lipid-soluble compounds. Male mice of three strains accumulated greater amounts of hepatic protoporphyrin than females after treatment with griseofulvin, yet no significant difference was found between the two sexes in the extent of ferrochelatase inhibition. Stimulation of ALA-S activity was slightly greater in males, but when porphyria was very marked, ALA-S activities were significantly lower in this sex.(ABSTRACT TRUNCATED AT 250 WORDS)
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