Microbial models

Smith RV. Rosazza J.P. (1975) Microbial models of mammalian metabolism. Pharm Sci, 64, 1737-1759. 

Rosazza JP, Rammer M, Youel L (1977) Microbial models of mammalian metabolism 0-demethylations of papaverine. Xenobiotica 7(3) 133-143... 

Azerad R (1999) Microbial models for drug metabolism. Adv Biochem Eng Biotechnol 63 169-218... 

Lacroix 1, Biton J, Azerad R (1999) Microbial models of drug metabolism microbial transformations of trimegestone (RU 27987), a 3-keto-delta(4,9(10))-19-norsteroid drug. Bioorg Med Chem 7(11) 2329-2341... 

Moussa C et al. (1997) Microbial models of mammalian metabolism. Fungal metabolism of phenolic and nonphenolic p-cymene-related drugs and prodrugs. 11. Metabolites of nonphenolic derivatives. Drug Metab Dispos 25(3) 311-316... 

In the 1970s, Smith and Rosazza introduced the concept of microbial models of mammalian metabolism [38,39]. Two reviews in this area were published in 1999 [40,41]. Since these, there have been numerous reports describing the use of microbial biotransformation in drug metabolism studies [42-54]. These reports demonstrated that microbial enzymes were able to... 

Abourashed, E.A., Clark, A.M. and Hufford, C.D. (1999) Microbial models of mammalian metabolism of xenobiotics an updated review. Current Medicinal Chemistry, 6, 359-374. 

Azerd, R. (1999) Microbial models for the drug metabolism. Advances in Biochemical Engineering/Biotech-nology, 63, 169-218. 

Rao, G.P. and Davis, P.J. (1997) Microbial models of mammalian metabolism biotransformation of HP 749 (besipirdine) using Cunninghamella elegans. Drug Metabolism and Disposition The Biological Fate of Chemicals, 25, 709-715. 

Lacroix, I., Biton, J. and Azerad, R. (1999) Microbial Models of drug metabolism microbial transformations of Trimegestone (RU27987), a 3-keto-A4 9 101-19-norstcroid drug. Bioorganic and Medicinal Chemistry, 7, 2329-2341. 

The concept of microbial models of mammalian metabolism was elaborated by Smith and Rosazza for just such a purpose (27-32). In principle, this concept recognizes the fact that microorganisms catalyze the same types of metabolic reactions as do mammals (32), and they accomplish these by using essentially the same type of enzymes (29). Useful biotransformation reactions common to microbial and mammalian systems include all of the known Phase I and Phase II metabolic reactions implied, including aromatic hydroxylation (accompanied by the NIH shift), N- and O-dealkylations, and glucuronide and sulfate conjugations of phenol to name but a few (27-34). All of these reactions have value in studies with the alkaloids. 

Strategy in Using Microbial Models of Mammalian Metabolism. In... 

Smith and Rosazza have suggested that microbial transformation experiments could best be carried out by using a series of perhaps 10 metabolitically prodigious microorganisms as microbial models. Microorganisms for such work may be selected on the basis of considerable literature precedence for their abilities to catalyze the desired biotransformation reaction (i.e., O-dealkylation, N-dealkylation, aromatic hydroxylation, and reductions). The alkaloid substrate... 

Recent work in our laboratories has confirmed the existence of a similar pathway in the oxidation of vindoline in mammals (777). The availability of compounds such as 59 as analytical standards, along with published mass spectral and NMR spectral properties of this compound, served to facilitate identification of metabolites formed in mammalian liver microsome incubations. Two compounds are produced during incubations with mouse liver microsome preparations 17-deacetylvindoline, and the dihydrovindoline ether dimer 59. Both compounds were isolated and completely characterized by spectral comparison to authentic standards. This work emphasizes the prospective value of microbial and enzymatic transformation studies in predicting pathways of metabolism in mammalian systems. This work would also suggest the involvement of cytochrome P-450 enzyme system(s) in the oxidation process. Whether the first steps involve direct introduction of molecular oxygen at position 3 of vindoline or an initial abstraction of electrons, as in Scheme 15, remains unknown. The establishment of a metabolic pathway in mammals, identical to those found in Strep-tomycetes, with copper oxidases and peroxidases again confirms the prospective value of the microbial models of mammalian metabolism concept. 

Bloss, T., Clemens, S. and Nies, D. H. (2002). Characterization of the ZATlp zinc transporter from Arabidopsis thaliana in microbial model organisms and reconstituted proteoliposomes, Planta, 214, 783-791. 

Alexandre, V., Ladril, S., Maurs, M. and Azerad, R., Microbial models of animal drug metabolism Part 5. Microbial preparation of human hydroxylated metabolites of irbesartan. J. Mol. Catal. B Enzymatic, 2004, 29, 173-179. 

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