Figure 1.

Survival rates, body weights, and liver-weight-per-total-body-weight ratio. Survival rates (A) during exposure to oral BaP at 12.5 mg/kg/day (N = 8 per genotype). Cyp1(+/+) wild-type (closed circles) are compared with Cyp1a1(−/−) knockout (open circles) and Cyp1a1/1b1(−/−) double-knockout (open squares) mice. At every oral BaP dose tested, Cyp1a1(−/−) mice always show significantly (P<0.001) more toxicity than Cyp1a1/1b1(−/−) mice⁹. This is because CYP1A1 is the major inducible CYP in the GI tract and, with oral BaP in Cyp1(+/+) wild-type mice, CYP1A1 becomes so highly induced that there is major detoxication and elimination of BaP metabolites in the feces. Without CYP1A1 in the GI tract in Cyp1a1(−/−) mice, at least 25-fold higher amounts of oral BaP reach distal tissues, including the spleen-thymus-bone marrow where BaP causes CYP1B1-dependent immunosuppression. Without CYP1A1 and CYP1B1 in the GI tract of Cyp1a1/1b1(−/−) mice, at least 75-fold higher amounts of oral BaP reach distal tissues; however, BaP is ineffective at causing immunosuppression because there is no CYP1B1 in the spleen-thymus-bone marrow to metabolize BaP to reactive oxygenated intermediates⁹. Similar to wild-type mice, no Cyp1b1(−/−) deaths were seen during the 26-week experiment (not shown). Body weights (B) and liver-weight-per-total-body-weight ratios (C) in the four genotypes, following corn oil alone (open bars) versus oral BaP at 12.5 mg/kg/day (closed bars) for 12 weeks. Cyp1a1(−/−) and Cyp1b1(−/−) single-knockout and Cyp1a1/1b1(−/−) double-knockout were compared with Cyp1(+/+) wild-type. *P<0.05. ^†P =.025.