Genotypesa | Cyp1(+/+), Cyp1a2(−/−), Cyp1b1(−/−), Cyp1a2/1b1(−/−) | Cyp1a1(−/−), Cyp1a1/1a2(−/−) | Cyp1a1/1b1(−/−), Cyp1a1/1a2/1b1(−/−) |
---|---|---|---|
Clinical outcome | Healthy for lifetime | Dies 28–32 d | Reverts almost completely to wild-type phenotype |
Blood BaP levels (ng/ml)b | ∼2.0 | ∼50 | ∼150 |
ALT, AST,c hemoglobin, hematocrit, methemoglobin levels | Normal | Abnormal | Near normal |
Bone marrow, spleen | Normal | Severe hypocellularity | Slight hypocellularity |
Liver, thymus | Normal | AHR activationd | AHR activationd |
↵a The knockout genotypes in all lines were backcrossed into C57BL/6J (B6) mice at least 8 times, rendering all animals with >99.8% B6 genetic background; hence, B6 inbred mice were used as Cyp1(+/+) controls. These data are summarized from Uno et al. (2004, 2006) and Dragin et al. (2007).
↵b Measured after 125 mg/kg/d of oral BaP for 5 days. All other parameters were described after oral BaP at this dose was given for 18 days.
↵c Plasma alanine aminotransferase (ALT) levels are to assess hepatocellular injury; plasma aspartate aminotransferase (AST) levels also are to assess liver injury but can also be a sign of cardiac and skeletal muscle damage.
↵d Activation reflects the fact that daily BaP treatment causes chronic AHR activation, which in turn leads to proliferation of the endoplasmic reticulum and increased liver weight and thymus weight; these effects are AHR-dependent but are independent of CYP1 metabolism (Uno et al., 2006).