Abstract
BackgroundThis study was performed to characterize a gene-addition transgenic mouse containing a BAC (bacterial artificial chromosome) clone spanning the human CYP2C18&19 genes (tg-CYP2C18&19).MethodsHemizygous 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.ResultsIn 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).ConclusionDespite 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.
Highlights
This study was performed to characterize a gene-addition transgenic mouse containing a BAC clone spanning the human CYP2C18&19 genes
Minimal perivascular infiltration of neutrophils was found on microscopic examination in the epididymal fat in one tg-CYP2C18&19 male and minimal alveolar histiocytosis was present in one tg-CYP2C18&19 female
All these changes were considered to belong to the spontaneous background pathology observed in laboratory mice of the C57BL/6JOlaHsd strain
Summary
This study was performed to characterize a gene-addition transgenic mouse containing a BAC (bacterial artificial chromosome) clone spanning the human CYP2C18&19 genes (tg-CYP2C18&19). The human cytochrome P450 enzymes from the 2C subfamily (CYP2C) are fairly well characterized and are known to metabolise many clinically important drugs. 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. CYP2C19 stereo-selectively metabolises the S-enantiomer of the anticonvulsant mephenytoin to the metabolite 4hydroxy- (S)-mephenytoin [8], and this metabolite is (page number not for citation purposes)
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