The screening of selected microorganisms for use as models of mammalian drug metabolism

Abstract

Fifty fungi and two Streptomyces species were screened for their ability to metabolise the probe substrates aminopyrine, diazepam, testosterone, theophylline and warfarin. The metabolism of the 14C-labelled substrates by whole growing cells was compared with that by rat liver microsomes using TLC-autoradiography. Testosterone, warfarin and diazepam were readily metabolised by most microorganisms, and aminopyrine and theophylline were only metabolised by a few. A relationship between substrate lipophilicity and number of microorganisms able to biotransform the substrate was observed, lipophilic substrates being favoured for metabolism, analagous to mammalian cytochrome P-450. A wide variety of metabolites were produced by the screened cultures, with a significant number co-chromatographing with mammalian metabolites. Most microorganisms appeared to exhibit cytochrome P-450-type oxidative reactions such as hydroxylation and N-demethylation, similar to mammalian hepatic microsomal cytochrome P-450 systems.

Cytochrome P450 Enzyme Systems in Fungi

“…Some PAHs, such as benzϽaϾpyrene, are known to be potent carcinogens (Pelkonen and Nebert, 1982;Autrup, 1990). The ability of different filamentous fungi, such as Cunninghamella elegans, C. bainieri, Mortierella isabellina, and Beauveria bassiana to hydroxylate one or more PAHs is well studied (Sutherland, 1992;Cerniglia et al, 1982Cerniglia et al, , 1992Cerniglia, 1984;Griffiths et al, 1991Griffiths et al, , 1993Holland et al, 1987Holland et al, , 1994Holland, 1992). Two different screening experiments have been described which were specifically aimed at the isolation of PAH-degrading fungi from the environment.…”

Transformations of testosterone and related steroids in Absidia glauca culture

“…Microbial transformations can be carried out giving higher yields at lower costs than chemical methods (SEDLACZEK 1988). They can also be used for model mammalian metabolism of steroid hormones, their synthetic analogues and other xenobiotics (SMITH et al 1975, GRIFFITHS et al 1991, LACROIX et al 1999. Selected microbial cultures may be exploited to produce, on a preparative scale, known or suspected mammalian metabolites of these compounds.…”

Biosynthesis of the RNA Polymerase Inhibitor Streptolydigin in Streptomyces lydicus: Tailoring Modification of 3-Methyl-Aspartate

“…In particular, drug N demethylases have been reported from Streptomyces griseus ATCC 13273 (5), Streptomyces platensis NRRL2364 (4), and other Streptomyces spp. (11).…”