Yeast as a Humanized Model Organism for Biotransformation-Related Toxicity

Abstract

High drug attrition rates due to toxicity, the controversy of experimental animal usage, and the EU REACH regulation demanding toxicity profiles of a high number of chemicals demonstrate the need for new, in vitro toxicity models with high predictivity and throughput. Metabolism by cytochrome P450s (P450s) is one of the main causes of drug toxicity. As some of these enzymes are highly polymorphic leading to large differences is metabolic capacity, isotype-specific test systems are needed. In this review, we will discuss the use of yeast expressing (mammalian) P450s as a powerful, additional model system in drug safety. We will discuss the various cellular model systems for bioactivation-related toxicity and subsequently describe the properties of yeast as a model system, including the endogenous bioactivation enzymes present, the heterologous expression of (mammalian) P450s and the application of yeasts expressing heterologous P450s and/or other biotransformation enzymes in toxicity studies. All major human drug-metabolizing P450s have been successfully expressed in yeast and various mutagenicity tests have been performed with these humanized yeast strains. The few examples of non-mutagenic toxicity studies with these strains and of the combination of P450s with phase II or other human enzymes show the potential of yeast as a model system in metabolism-related toxicity studies. The wide variety of genome-wide screens available in yeast, combined with its well-annotated genome, also facilitate follow-up studies on the genes involved in toxicity. Unless indicated otherwise "yeast" will refer to baker's yeast Saccharomyces cerevisiae.

Differences of Cytotoxicity of Orthodontic Bands Assessed by Survival Tests inSaccharomyces cerevisiae

“…The experimental model S. cerevisiae has been widely used in biomedical research studies, with very diverse objectives and applications, from cellular biology involved in genetic and neurological diseases [43] to toxicological surveys [44]. The broad applicability of this yeast species as a model organism is based on its easy cell cycle control, great facility of biochemical and genetic manipulation, short time, and inexpensive reproducible experiments [45] as well as biochemical and genetic similarity to animal cells [26, 27].…”

Identification of auxotrophic mutants of the yeast Kluyveromyces marxianus by non‐homologous end joining‐mediated integrative transformation with genes from Saccharomyces cerevisiae

“…In contrast to S. cerevisiae and K. lactis, which are widely used for molecular biology and industrial applications (Mattiazzi et al, 2012;Schaffrath and Breunig, 2000;Schwimmer et al, 2006;Smith and Snyder, 2006;van Leeuwen et al, 2012), K. marxianus has received relatively little attention, although there are an increasing number of reports describing the potential application of K. marxianus for the production of ethanol, biomass, endogenous enzymes and aromatic compounds (Bansal et al, 2008;Fonseca et al, 2008;Gao and Daugulis, 2009;Limtong et al, 2007;Nonklang et al, 2008Nonklang et al, , 2009Rodrussamee et al, 2011;Wittmann et al, 2002) and for protein structural analysis (Watanabe et al, 2012;Yamaguchi et al, 2012aYamaguchi et al, , 2012b. Thus, in the present study, we generated and characterized 79 auxotrophic mutants and identified 35 complementing genes using a novel integrative transformation approach for the development of genetic tools in K. marxianus.…”

The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae

“…The budding yeast Saccharomyces cerevisiae is frequently used to study drug-induced toxicity [18,19]. Although it is a simple eukaryotic cell with approximately 6000 genes, many essential pathways are highly conserved between human and yeast.…”