Few alterations in clinical pathology and histopathology observed in a CYP2C18&19 humanized mice model

Hemizygous tg-CYP2C18&19, 11 week old mice were compared with wild-type littermates to obtain information regarding clinical status, clinical pathology and anatomical pathology. After one week of clinical observations, blood samples were collected, organs weighed, and tissues collected for histopathology.In males, the tissue weights were lower in tg-CYP2C18&19 than in wild-type mice for brain (p ≤ 0.05), adrenal glands (p ≤ 0.05) and brown fat deposits (p ≤ 0.001) while the heart weight was higher (p ≤ 0.001). In female tg-CYP2C18&19, the tissue weights were lower for brain (p ≤ 0.001) and spleen (p ≤ 0.001) compared to wild-type females. Male tg-CYP2C18&19 had increased blood glucose levels (p ≤ 0.01) while females had decreased blood triglyceride levels (p ≤ 0.01).Despite the observed alterations, tg-CYP2C18&19 did not show any macroscopic or microscopic pathology at the examined age. Hence, these hemizygous transgenic mice were considered to be viable and healthy animals.The human cytochrome P450 enzymes from the 2C subfamily (CYP2C) are fairly well characterized and are known to metabolise many clinically important drugs. Four members belonging to the CYP2C family are found in man, namely CYP2C8, CYP2C9, CYP2C18 and CYP2C19 [1]. The anticancer drug paclitaxel is metabolised by CYP2C8 and the 6-hydroxylation of this compound is commonly used as a marker for this enzyme [2]. CYP2C9 metabolises many drugs, for example the hypoglycaemic drug tolbutamide [3], the anticonvulsant phenytoin [3,4], the anticoagulant warfarin [5] and a number of nonsteroidal anti-inflammatory drugs including diclofenac and ibuprofen [6], which have all been used as marker substrates. The CYP2C18 protein has not yet been found in detectable amounts in any tissues [7], and its in vivo function is, to date, unknown. CYP2C19 stereo-selectively metabolises the S-enantiomer of the anticonvulsant mephenytoin to the metabolite 4-hydroxy- (S)-mephenytoin [8], and this metabolite is commonly measur