The search for in vitro systems that can precisely simulate the processes that prevail in the in vivo situation is a continuous and a challenging one. A number of in vitro systems, employing both animal and human tissue, are currently being used to enable the pharmaceutical, agrochemical and other industries to study the metabolism of new chemical entities at an early stage of compound development. Such systems may also be employed to define the toxic potential and to assess the human risk of such chemicals. For example, primary hepatocytes have emerged as a commonly used system for assessing the metabolism and toxicity of chemicals and this system has been recommended by many government organisations. However, a major drawback is that this system employs a single cell type. While hepatocytes have a major role in xenobiotic metabolism and toxicity in the liver, such an approach would be unsuitable for addressing metabolism and toxicity of chemicals in multicellular organs such as the lung, where more than one cell type can contribute to xenobiotic metabolism and toxicity. The use of precision-cut slices overcomes this problem as it maintains the architecture of the tissue so that all cell types are present and intercellular communication is retained.
The use of slices in research is by no means a novel development; they have been successfully used at the beginning of the 20th century by, among others, Warburg and Krebs to unravel the pathways of carbohydrate metabolism. Slices were cut by hand using a razor blade, and this inevitably led to variable thickness that compromised their performance and led to extensive variability. The development by Carlos Krumdieck and co-workers of a ‘live tissue microtome’ that could readily generate viable slices of uniform thickness with minimal damage to the tissue, re-ignited interest in this system. The successful cryopreservation of slices, of particular importance when utilising human tissues, has further extended the usefulness and applicability of this system. As a result, the use of slices, in reality a ‘mini tissue’, is emerging as a viable competitor to other available in vitro systems for the study of xenobiotic metabolism and toxicity and hence merits serious consideration by the scientific community and regulatory bodies.
The purpose of this special issue of Xenobiotica, devoted to precision-cut tissue slices, is to bring together, under the same cover, detailed contributions by researchers with expertise in this area to inform scientists involved in the development of new chemical entities of the versatility of this in vitro system and highlight its potential applications. The first paper by Carlos Krumdieck is a historical perspective and describes the development of the Krumdieck tissue slicer. Methods for the preparation and culture of precision-cut slices from the liver and other tissues from experimental animals and human are reviewed by Fisher and Vickers. Various applications of tissue slices are discussed in the subsequent eight chapters. The use of precision-cut slices for studies of induction of phase I and II xenobiotic-metabolising enzymes is reviewed by Ioannides and the use of tissue slices to elucidate drug-induced toxicity in humans is addressed by Vickers and Fisher. Lake and Price describe the use of precision-cut liver slices in studies of xenobiotic metabolism and toxicity, whereas the use of precision-cut kidney slices in nephrotoxicity studies is considered by Baverel and co-workers. The next contribution by Morin and colleagues focuses on precision-cut lung slices and their use in physio-pharmaco-toxicology studies. Niu and co-workers discuss the use of precision-cut slices to evaluate the intestinal metabolism, toxicity and transport of xenobiotics, and Sewald and Braun describe how precision-cut tissue slices can be employed to assess immunotoxicity. The final paper in this special issue by Fahy and co-workers deals with the cryopreservation of precision-cut tissue slices.
We hope that this special issue of Xenobiotica will stimulate interest in the precision-cut tissue slice technique as an alternative in vitro model system for studying the metabolism and toxicity of xenobiotics in a range of tissues. The various papers in this special issue also highlight a major advantage of this technique in that it can be readily applied to studies with human tissue in order to assess species differences in response.
Declaration of interest
The authors declare no conflicts of interest.