Genetic variation in the response of mice to xenobiotics, in vitro.

Adverse reactions to drugs and environmental chemicals are a serious problem with up to 30% of hospital patients experiencing such problems (Venning, 1983; Ludwig and Axelsen, 1983). There is evidence that many adverse reactions arise as a result of genetically controlled sensitivity (Festing, 1987). Large genetically determined differences in response to chemicals have also been recorded in laboratory animals. However, most toxicological screening involves a single strain and fails to detect genetically determined sensitivity. Should some animals show an adverse reaction, this is usually attributed to "biological variation". As the pedigree of such animals is not normally known at the time of use there is no way of showing whether these adverse reactions were inherited (Festing, 1975, 1979). The initial aim of this project was to develop a technique for studying genetic variation in sensitivity to treatment with drugs using in vitro screening methods. The techniques should not require hazardous or expensive chemicals and equipment, should require a small number of animals and should be reliable and easy to perform. Several end-points were studied, and a protocol for detecting genetic differences which included four end-points and two cell types was developed. In the second part of the project, the aim was to study genetic variation in sensitivity to Aspirin, Ethanol and Coumarin as model compounds, using the previously developed techniques in conjunction with suitable genetically-defined strains of mice. Two cell types (macrophages and hepatocytes) were studied and several end-points were used including neutral red uptake, total protein concentration, rate of phagocytosis and LDH activity in cells and supernatant. The study involved nine strains of mice. Although statistically significant differences among inbred strains were detected, in no experiment did strain distribution pattern suggest single-locus Mendelian control. There was no evidence that response to coumarin depended on the coumarin hydroxylase (Cyp2b) locus nor that response to alcohol depended on the alcohol dehydrogenase locus. It is concluded that further development would be necessary to develop these methods as a way of identifying genes associated with their type of genetic variation.