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Applied and Environmental Microbiology, May 2003, p. 2884-2892, Vol. 69, No. 5
0099-2240/03/$08.00+0     DOI: 10.1128/AEM.69.5.2884-2892.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Recombinant Saccharomyces cerevisiae Expressing P450 in Artificial Digestive Systems: a Model for Biodetoxication in the Human Digestive Environment

S. Blanquet,1 J. P. Meunier,1 M. Minekus,3 S. Marol-Bonnin,2 and M. Alric1*

Equipe de Recherche Technologique ‘Conception, Ingénierie et Développement de l'Aliment et du Médicament,’ Centre de Recherche en Nutrition Humaine, Faculté de Pharmacie, Université d'Auvergne, 63001 Clermont-Ferrand,1 Digestar SA, Biopôle Clermont-Limagne, 63360 Saint-Beauzire, France,2 TNO Nutrition and Food Research Institute, 3700 AJ Zeist, The Netherlands3

Received 15 April 2002/ Accepted 30 January 2003

The use of genetically engineered microorganisms such as bacteria or yeasts as live vehicles to carry out bioconversion directly in the digestive environment is an important challenge for the development of innovative biodrugs. A system that mimics the human gastrointestinal tract was combined with a computer simulation to evaluate the survival rate and cinnamate 4-hydroxylase activity of a recombinant model of Saccharomyces cerevisiae expressing the plant P450 73A1. The yeasts showed a high level of resistance to gastric and small intestinal secretions (survival rate after 4 h of digestion, 95.6% ± 10.1% [n = 4]) but were more sensitive to the colonic conditions (survival rate after 4 h of incubation, 35.9% ± 2.7% [n = 3]). For the first time, the ability of recombinant S. cerevisiae to carry out a bioconversion reaction has been demonstrated throughout the gastrointestinal tract. In the gastric-small intestinal system, 41.0% ± 5.8% (n = 3) of the ingested trans-cinnamic acid was converted into p-coumaric acid after 4 h of digestion, as well as 8.9% ± 1.6% (n = 3) in the stomach, 13.8% ± 3.3% (n = 3) in the duodenum, 11.8% ± 3.4% (n = 3) in the jejunum, and 6.5% ± 1.0% (n = 3) in the ileum. In the large intestinal system, cinnamate 4-hydroxylase activity was detected but was too weak to be quantified. These results suggest that S. cerevisiae may afford a useful host for the development of biodrugs and may provide an innovative system for the prevention or treatment of diseases that escape classical drug action. In particular, yeasts may provide a suitable vector for biodetoxication in the digestive environment.

* Corresponding author. Mailing address: ERT CIDAM, Faculté de Pharmacie, CRNH, Université d'Auvergne, 28, place Henri Dunant, 63001 Clermont-Ferrand, France. Phone: 33 (0) 4 73 17 79 52. Fax: 33 (0) 4 73 27 56 24. E-mail: Monique.ALRIC{at}crnh.u-clermont1.fr.

Applied and Environmental Microbiology, May 2003, p. 2884-2892, Vol. 69, No. 5
0099-2240/03/$08.00+0     DOI: 10.1128/AEM.69.5.2884-2892.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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