All Phenotypes Cyp2a12<em1Utr> MGI Mouse

premature death ( J:302190 )

• unexpected death within a week of weaning (4 weeks of age) is seen in 20-25% of mice

• however, growth of surviving mice is good at least until 11 weeks of age

reduced fertility ( J:302190 )

• fertility is slightly lower

increased liver weight ( J:302190 )

• liver weight is increased in both sexes

decreased intestinal cholesterol absorption ( J:302190 )

• intestinal cholesterol absorption, as estimated by serum sitosterol and campesterol, is reduced

increased circulating alanine transaminase level ( J:302190 )

• in males

increased circulating alkaline phosphatase level ( J:302190 )

• in males

abnormal bile salt homeostasis ( J:302190 )

• deoxycholic acids (DCAs), chenodeoxycholic acids (CDCAs), and lithocholic acids (LCAS) are increased in the tissues

• total bile acid pool is reduced by approximately 50% in both sexes

• hepatic bile acid content is elevated in females

• fecal bile acid concentration is decreased

• hepatic activity of key enzyme in bile acid biosynthesis is reduced, with CYP7A1 enzyme activity decreased by more than 50% in males and more than 80% in females and CYP7B1 enzyme activity decreased by about 60% in males and about 50% in females

• however, CYP8B1 and CYP27A1 enzyme activity are not affected

decreased bile salt level ( J:302190 )

• total bile acid pool is reduced by approximately 50% in both sexes

abnormal cholesterol homeostasis ( J:302190 )

• serum 4beta-hydroxycholesterol is elevated

• liver desmosterol level in males is increased

decreased circulating cholesterol level ( J:302190 )

• serum total cholesterol concentration is decreased by 24% in males

• however, liver total cholesterol concentrations are unchanged and no change in serum and liver triglyceride concentrations are seen

abnormal enzyme/coenzyme activity ( J:302190 )

• taurodeoxycholic acid (TDCA) 7alpha-hyddroxylase activity in the liver is reduced to approximately 10% of wild-type levels

• taurochenodeoxycholic acid (TCDCA) 6beta-hydroxylase activity is almost absent in the liver

• CYP7A1 enzyme activity is decreased by more than 50% in males and more than 80% in females

• CYP7B1 enzyme activity is decreased by about 60% in males and about 50% in females

• however, CYP8B1 and CYP27A1 enzyme activity are not affected

abnormal bile duct morphology ( J:302190 )

• males show a slight bile ductular reaction in the liver, but necrosis of hepatocytes is not seen

abnormal liver morphology ( J:302190 )