Microbial models of mammalian metabolism: uses and misuses (clarification of some misconceptions)

https://doi.org/10.1016/S1381-1177(98)00089-7Get rights and content

Abstract

Oxidative metabolism is the most commonly encountered metabolic clearance pathway of xenobiotics by mammalian systems. Similar pathways are often encountered in microorganisms and have been used to metabolise xenobiotics. This paper reviews the background to these observations and the potential uses they imply. It proposes that although microbial metabolism can have a useful role in preparative biocatalysis, any predictive value to man is negated by the lack of correlation with mammalian systems and may potentially be misleading.

Introduction

Oxidative metabolism is the most commonly encountered metabolic clearance pathway for drugs in animals and man 1, 2. This metabolism is often carried out by a super-family of enzymes: the cytochrome P450s (CYPs) and many CYPs have now been gene sequenced for man (>40) and other species (>200) [3]. Such enzymes are not specific to animals, but are also found in plants and, more relevantly here, in microorganisms. Microorganisms have been extensively investigated as a tool to provide mechanistic insight or for their biocatalytic properties and there are many reports of drugs which are successfully metabolised by microorganisms: warfarin, propranolol, phenacetin, quinidine, carbamazepine, ibuprofen, phenytoin, diazepam, aminopyrene, theophilline, tamoxifen, sulindac, imipramine, etc. The use of microorganisms appeals as a potentially very useful tool in the design of novel drugs. However; two key questions must be asked: can useful and reliable predictions be made from microbial systems and can they be used as reliable biocatalytic reagents?

Section snippets

Metabolism by mammalian systems

The mammalian CYPs responsible for the metabolism of xeno- and endobiotics are a super-family of membrane bound, heme-containing enzymes. They are found in many organs in low concentrations but reside mainly in high levels in hepatic tissues and intestinal epithelium. A fundamental property of metabolic reactions carried out by CYPs is that they are all based on electrophilic attack (Table 1) [4].

For all CYPs, the different types of `oxidative metabolism' (hydroxylation, de-alkylation,

Applications of microbial CYPs

Since the early days of Smith and Rosazza [14]when the basic principles of microbial modelling of mammalian metabolism were set out, much research has been undertaken to characterise this approach. Most of this research has led to factual reporting of microbial biocatalysis results, and although their predictive capabilities are occasionally mentioned, it seems always to be as a generic or throw away comment usually in the introduction. There are many literature examples of microorganisms being

Are microbial biotransformations predictive of human drug metabolism?

At first sight, there appear to be a lot of commonality between all CYPs. But does this include reliable commonality of metabolic pathways of xenobiotics?

One of the most frequently reported substrate which is metabolised by both mammalian and microbial CYPs is warfarin. This drug has, therefore, been used to examine any overlap of metabolism patterns between mammalian and microbial CYPs.

The human metabolism of warfarin is summarised in Fig. 4, with relevant specificity of individual CYPs.

In

References (31)

  • D.A. Smith et al.

    Biochem. Pharmacol.

    (1992)
  • D.R. Nelson et al.

    DNA Cell Biol.

    (1993)
  • D.A. Smith et al.

    Med. Res. Dev.

    (1996)
  • T.L. Poulos et al.

    J. Biol. Chem.

    (1985)
  • T.L. Poulos et al.

    J. Mol. Biol.

    (1987)
  • J.A. Peterson et al.

    J. Biol. Chem.

    (1992)
  • R.V. Smith et al.

    Arch. Biochem. Biophys.

    (1974)
  • J.D. Rizzo et al.

    J. Pharm. Sci.

    (1989)
  • Y.W. Wong et al.

    J. Pharm. Sci.

    (1991)
  • S. Rendic et al.

    Drug Metab. Rev.

    (1997)
  • F.P. Guengerich

    Prog. Drug Metab.

    (1987)
  • S.P. Crammer et al.

    J. Am. Chem. Soc.

    (1978)
  • J.A. Peterson, S.E. Graham-Lorence, in: P. Ortiz de Montellano (Ed.), Cytochrome P450, Plenum, 1995, p....
  • A.J. Fulco

    Annu. Rev. Pharmacol. Toxicol.

    (1991)
  • C.A. Hitchcok et al.

    Biochem J.

    (1989)
  • Cited by (18)

    • Pharmaceutical significance and recent developments in utilizing bacterial enzymes

      2020, Recent Developments in Applied Microbiology and Biochemistry: Volume 2
    • Biosynthesis of human diazepam and clonazepam metabolites

      2015, Bioorganic and Medicinal Chemistry Letters
    • Facile production of minor metabolites for drug development using a CYP3A shuffled library

      2011, Metabolic Engineering
      Citation Excerpt :

      Cytochrome P450 enzymes sourced from microbial species are well established as biocatalysts in the pharmaceutical industry (Hogg, 1992; Manzoni and Rollini, 2002; Peterson, 1952; Petzoldt et al., 1982; Urlacher and Eiben, 2006). Microbial species have been screened for the ability to make metabolites that could not be produced efficiently in sufficient quantities by chemical means (e.g. Jezequel, 1998; Li et al., 2008) and references therein). CYP102A1 from Bacillus megaterium has also been used to generate significant quantities of major metabolites (Kim et al., 2009).

    • Bacterial production of hydroxylated and amidated metabolites of flurbiprofen

      2011, Journal of Molecular Catalysis B: Enzymatic
      Citation Excerpt :

      Microorganisms can metabolise pharmaceutical compounds in a similar fashion to animals, and thus can act as models of drug metabolism [1]. Furthermore, the ease of scaling-up microbial cultures has the potential of generating sufficient quantities of drug metabolites that might also be required for in vivo testing [2,3]. The fungus Cunninghamella elegans has been a particular focus for investigations on drug transformations [4], as it is known to generate oxidative (phase I) and conjugative (phase II) metabolites.

    View all citing articles on Scopus
    View full text