Microbial models of mammalian metabolism: Involvement of cytochrome P450 in the N-demethylation of N-methylcarbazole by Cunningham ella echin ula ta

Abstract

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.

Nonaqueous capillary electrophoretic separation and thermo‐optical absorbance detection of five tricyclic antidepressants and metabolism of amitriptyline by Cunninghamella elegans

“…These fungi metabolize drugs in a manner similar to that in mammals. For example, cytochrome P450 monooxygenases are involved in the oxidative drug metabolism reactions in both fungi and mammals [41][42][43]. Therefore, fungal metabolism could model mammalian drug metabolism.…”

Multifunctional oligoetherols and polyurethane foams with carbazole ring

“…Carbazole and its derivatives are used in chemistry and technology of polymers, dyes, pesticides, drugs, surfactants, stabilizers and other additives for plastics [1][2][3][4][5][6][7] . Some of derivatives were demonstrated to have unique physical properties like photo-and electroluminescence, liquid crystallinity, electric conductivity, and non-linear optics 8- 14 .…”

Hydroxylation of carbazoles by Aspergillus flavus VKM F-1024

“…For example, the composition of N-methylcarbazole products by Cunninghamella strains was different as compared with that of CZ [15,16]. The N-benzoyl substitution of indole allowed the obtaining of 4-hydroxyindole [17].…”

“…As distinct from bacterial degradation, little is known about CZ metabolism by these organisms [15,16,18]. In this work, 3-HCZ was assigned to be a major metabolite at CZ conversion by A. flavus F-1024.…”