title: Labelling in vivo and chirality of griseofulvin-derived N-alkylated protoporphyrins.
abstract: 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.
authors.affiliation: MRC Toxicology Unit, MRC Laboratories, Carshalton, Surrey, U.K.
authors.forename: F
authors.initials: F
authors.lastname: De Matteis
authors.forename: A H
authors.initials: AH
authors.lastname: Gibbs
authors.forename: S R
authors.initials: SR
authors.lastname: Martin
authors.forename: R L
authors.initials: RL
authors.lastname: Milek
mesh_terms: 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
chemical_list: D011524:Protoporphyrins; D006118:Griseofulvin; C028842:N-methylprotoporphyrin IX; D003577:Cytochrome P-450 Enzyme System