Labelling in vivo and chirality of griseofulvin-derived N-alkylated protoporphyrins.
1. We have compared the response to griseofulvin of rats and mice and, in mice, the effect of griseofulvin itself with that of two of its analogues. The severity of protoporphyria shows a correlation with the accumulation of both types of N-alkylated porphyrins previously described after treatment with this drug, namely N-methylproptoporphyrin and the N-griseofulvin protoporphyrin adduct. 2. Both N-alkylporphyrins are chiral, are labelled from 5-amino[4-14C]laevulinate, and their liver accumulation can be inhibited by pretreatment with a suicide substrate of cytochrome P-450, which also prevents porphyria. 3. These findings suggest that cytochrome P-450 is involved in the mechanism of griseofulvin-induced protoporphyria by generating N-methylprotoporphyrin. The N-griseofulvin protoporphyrin adduct may also originate from cytochrome P-450, but more work is necessary to elucidate whether it acts as the precursor for N-methylprotoporphyrin.
De Matteis
F
F
MRC Toxicology Unit, MRC Laboratories, Carshalton, Surrey, U.K.
Gibbs
A H
AH
Martin
S R
SR
Milek
R L
RL
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006118:Griseofulvin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D011164:Porphyrias / Q000139:chemically induced*; D011524:Protoporphyrins / Q000096:biosynthesis* / Q000737:chemistry; D051381:Rats
D011524:Protoporphyrins; D006118:Griseofulvin; C028842:N-methylprotoporphyrin IX; D003577:Cytochrome P-450 Enzyme System