Xenobiotica. 1993 Sep;23(9):973-82.  

Microbial models of mammalian metabolism: involvement of cytochrome P450 in the
N-demethylation of N-methylcarbazole by Cunninghamella echinulata.

Yang W, Jiang T, Acosta D, Davis PJ.

Division of Medicinal and Natural Products Chemistry, College of Pharmacy,
University of Texas, Austin 78712.

1. As previously reported (Yang and Davis 1992), N-methylcarbazole (NMC) is
converted to N-hydroxymethylcarbazole (NHMC), and
3-hydroxy-N-hydroxymethylcarbazole (3-OH-NHMC), two relatively stable
carbinolamine metabolites by the fungus Cunninghamella echinulata (ATCC 9244).
Decomposition of these two carbinolamines yields the corresponding dealkylated
metabolites, carbazole and 3-hydroxycarbazole. In the present study, the
possible involvement of cytochrome P450 in the requisite N-alkyl hydroxylation
reaction was examined. 2. Carbon monoxide, a classical P450 inhibitor, markedly
inhibited the formation of NHMC, as did potassium cyanide. 1-Benzylimidazole,
piperonyl butoxide and SKF-525A inhibited the formation of both NHMC and
3-OH-NHMC, while beta-naphthoflavone (5,6-benzoflavone) induced their formation.
3. The source of the oxygen atom in the metabolite NHMC was examined by GC/MS
analysis of NHMC formed during incubation of NMC in H218O-enriched medium which
resulted in no incorporation of labelled oxygen into the metabolite. 4. An
intermolecular isotope effect was not observed for the formation of NHMC
suggesting that C-H bond cleavage is not a rate limiting step in the formation
of this metabolite under the conditions examined. 5. It was concluded that P450
enzymes may be involved in the N-demethylation of NMC catalyzed by this fungal
model of mammalian metabolism, and provides further support for biochemical and
mechanistic parallels between mammalian metabolism and microbial systems
catalyzing phase-1 biotransformations.

PMID: 8291265 [PubMed - indexed for MEDLINE]