Biotransformation of chlorpromazine and methdilazine by Cunninghamella elegans

Abstract

When tested as a microbial model for mammalian drug metabolism, the filamentous fungus Cunninghamella elegans metabolized chlorpromazine and methdilazine within 72 h. The metabolites were extracted by chloroform, separated by high-performance liquid chromatography, and characterized by proton nuclear magnetic resonance, mass, and UV spectroscopic analyses. The major metabolites of chlorpromazine were chlorpromazine sulfoxide (36%), N-desmethylchlorpromazine (11%), N-desmethyl-7-hydroxychlorpromazine (6%), 7-hydroxychlorpromazine sulfoxide (5%), and chlorpromazine N-oxide (2%), all of which have been found in animal studies. The major metabolites of methdilazine were 3-hydroxymethdilazine (35%), methdilazine sulfoxide (30%), methdilazine N-oxide (4%), phenothiazine (3%), and 2-hydroxymethdilazine (3%). 18 O 2 labeling experiments indicated that the oxygen atoms in methdilazine sulfoxide, methdilazine N-oxide, and 3-hydroxymethdilazine were all derived from molecular oxygen. The production of methdilazine sulfoxide and 3-hydroxymethdilazine was inhibited by the cytochrome P-450 inhibitors metyrapone and proadifen. An enzyme activity for the sulfoxidation of methdilazine was found in microsomal preparations of C. elegans. These experiments suggest that the sulfoxidation and hydroxylation of methdilazine and chlorpromazine by C. elegans are catalyzed by cytochrome P-450.

Cloning, sequencing, and expression inEscherichia coliof a cytochrome P450 gene fromCunninghamella elegans

“…We have shown earlier that the cytochrome P450 of C. elegans is involved in the metabolism and biotransformation of a number of xenobiotics [6–11]. In this paper, we present the cloning, sequencing, and expression of a cytochrome P450 gene of C. elegans .…”

“…C. elegans ATCC 36112 metabolizes or biotransforms numerous structurally diverse compounds, such as polycyclic aromatic hydrocarbons (PAHs), crude oil components, drugs, and N ‐, S ‐, O ‐heterocyclic aromatic compounds, by phase I and phase II enzymes [5]. The phase I reactions catalyzed by cytochrome P450 in C. elegans include aliphatic and aromatic hydroxylation, N ‐ and O ‐dealkylation and N ‐ and S ‐oxidation [5–11]. The involvement of cytochrome P450 enzymes in the metabolism of PAHs and pharmaceutical compounds by C. elegans is based on carbon monoxide difference spectra (absorption at 450 nm), enzyme activities, cytochrome P450 inhibitors, 18 O 2 incorporation experiments, and spectra of metabolites that are similar to those formed by mammalian cytochrome P450 enzyme systems [2,8,9].…”

Overview on the Biochemical Potential of Filamentous Fungi to Degrade Pharmaceutical Compounds

“…Thus, they represent a tool for emulating mammal drug metabolism and for manufacturing metabolites of industrial interest (Asha and Vidyavathi, 2009 ). The high capability of this fungus to transform a broad spectrum of compounds has been studied in lab scale and are represented on Figure 4 such as the diuretic furosemide (Hezari and Davis, 1993 ), the anti-inflammatory meloxican (Tevell Åberg et al, 2009 ), antibiotics such as fluoroquinolones (flumequine) (Williams et al, 2007 ), the pro-hormone adrenosterone (Choudhary et al, 2007 ), the anti-gastroesophageal reflux omeoprazol (Pearce and Lushnikova, 2006 ), the anticoagulant warfarin (Wong and Davis, 1989 ), antihistamines such as brompheniramine, chlorpheniramine, and pheniramine (Hansen et al, 1995 ), antipsychotics such as chlorpromazine and methdilazine (Zhang et al, 1996b ), the muscle relaxer cyclobenzaprine (Zhang et al, 1996a ), the anti-depressant mirtazapine (Moody et al, 2002 ) or the anticonvulsant carbamazepine (Kang et al, 2008 ). The biotransformation of PhACs by C. elegans , in general, undergo a phase I reaction (oxidation, reduction, and hydrolysis), generating hydroxylated metabolites, (2-hydroxycarbamazepine, hydroxyflumequine, hidroxywarfarin, etc.)…”

Antecedentes del estudio metabólico de MDPV y metilona. Propuesta de un modelo de biotransformación a través de hongos del género Cunninghamella

“…C. elegans posee la habilidad para degradar regio y estereo selectivamente diferentes clases de xenobióticos en metabolitos de fase I y fase II, de manera similar al sistema enzimático mamífero. Entre estos pueden ser mencionados varios fármacos [21][22][23][24][25][50][51][52][53][54][55][56][57], hidrocarburos poliaromáticos y contaminantes [58][59][60][61][62], drogas de abuso [63] y pesticidas [64][65][66] en metabolitos de fase I y fase II [36][37][38]. La mayoría de estos trabajos tienen como objetivo primordial el estudio del metabolismo mamario o la preparación de nuevos metabolitos activos, más que el estudio de detoxificación de los xenobióticos.…”