Epsilon Open Archive

Abstract

Drugs on the market continuously improve and target directed drugs become more and more common. Animal models are used to predict effects and side effects that may occur when drugs are administered to humans. The use of mice within medical testing is steadily increasing and the use of transgenic mouse models is also expanding. In this thesis, both traditional mouse strains, and a humanized CYP2C18/CYP2C19 transgenic mouse model is investigated. Initially, we found that cytochrome P450 (CYP) enzymes in the liver of traditional mouse strains are expressed with large strain and sex differences in both protein levels and metabolic activity. These differences contribute to the difficulties when extrapolating data to man from tests performed on animals. The CYP2C18/CYP2C19 transgenic mouse model investigated contains, in addition to the murine Cyp2c enzymes, the human CYP2C18 and CYP2C19 enzymes. Heterozygous CYP2C18/CYP2C19 transgenic mice were healthy animals, without obvious adverse phenotypic characteristics and were determined to possess approximately 12 tandem copies of the inserted CYP2C18/CYP2C19 gene segment. The inserted gene was translated into CYP2C18 and CYP2C19 mRNA and CYP2C19 protein more efficiently in male than in female mice livers, whereas no sex differences were found in small intestine, lung or brain. The enzymatic activity of CYP2C19 is also higher in males than in females. The sexually dimorphic, male predominant, CYP2C18 and CYP2C19 gene expressions, as well as the expression of female predominant, endogenous, mouse Cyp2c37, Cyp2c38, Cyp2c39 and Cyp2c40 genes were found to be dependent on androgens and the release pattern of growth hormone. In summary, large strain– and sex differences in CYP expression occur in mice. Sex differences in expression of CYP2C18 and CYP2C19 are evident in a transgenic mouse model containing human CYP2C18 and CYP2C19 genes. The sex dependent differences in expression are affected by gonadal hormones and growth hormone. The transgenic mouse model, may serve as a model for investigation of human CYP2C18 and CYP2C19 gene regulation.