The cytochrome P450 (CYP1A1) enzyme metabolically activates many polycyclic aromatic hydrocarbons, including benzo [a]pyrene (BaP), to DNA-and protein-binding intermediates that are associated with toxicity, mutagenesis, and carcinogenesis. As a result, it is widely accepted that CYP1A1 potentiates the toxicity of this class of chemicals. In distinct contrast, we show here that CYP1A1 inducibility is essential in the detoxication of oral BaP. We compared Cyp1a1(Ϫ/Ϫ) knockout mice, having the genetic absence of the CYP1A1 enzyme, with Cyp1a1(ϩ/ϩ) wild-type mice. At an oral BaP dose of 125 mg/ kg/day, Cyp1a1(Ϫ/Ϫ) mice died within 30 days whereas Cyp1a1(ϩ/ϩ) mice displayed no outward signs of toxicity. The rate of BaP clearance was 4-fold slower in Cyp1a1(Ϫ/Ϫ) than Cyp1a1(ϩ/ϩ) mice. The cause of death in Cyp1a1(Ϫ/Ϫ) mice receiving oral BaP seemed to be immunotoxicity, including toxic chemical depression of the bone marrow; some toxic effects in Cyp1a1(Ϫ/Ϫ) mice were noted at a BaP dose as low as 1.25 mg/kg/day. DNA post-labeling studies demonstrated dramatically higher BaP-DNA adduct levels in all Cyp1a1(Ϫ/Ϫ) tissues assayed, with the exception of the small intestine, which is probably a major site of BaP metabolism in Cyp1a1(ϩ/ϩ) mice. Different BaP-DNA adduct patterns were also observed between the two genotypes receiving oral BaP. Despite previous studies in vitro and in cell culture that have shown a participatory role for CYP1A1 in BaP toxicity, the present data indicate that, in the intact animal, inducible CYP1A1 is extremely important in detoxication and protection against oral BaP toxicity.

CYP1A1 and CYP1B1 metabolically activate many polycyclic aromatic hydrocarbons (PAHs), including benzo[a]pyrene, to reactive intermediates associated with toxicity, mutagenesis, and carcinogenesis. Paradoxically, however, Cyp1a1

Replacement of mouse Cyp1a2 with a functional human CYP1A2 gene restored the ability to metabolize theophylline, and the metabolism changed to a humanized profile (i.e. 3-methylxanthine formation, not seen in the wild-type mouse). TCDD-pretreated hCYP1A1_1A2 Cyp1a2(-/-) mice exhibited enhanced theophylline metabolism and clearance, due to induction of the human CYP1A2 enzyme. Comparing the hCYP1A1_1A2 Cyp1a2(-/-) and wild-type mice with published clinical studies, we found theophylline clearance to be about 5 times and 12 times, respectively, greater than that reported in humans.

Gingival overgrowth is a common health problem caused by genetic and environmental risk factors. Animal models for quantitative histological studies are needed to uncover genetic predisposition and dose-response data that might put individuals at increased risk for gingival disease. Gingival height, thickness, inflammation, and the degree of encroachment of gingiva over the tooth, are clinical measures of overgrowth; most of these parameters can be measured histologically, but in order to quantify gingival coverage of the tooth, the image of the crown must be present. Tooth and bone typically require decalcification for histology; thus, the tooth crown, a critical landmark, is lost. We describe a method for imaging the crown histologically, using impression materials applied to dissected mouse mandibles. Four dental alginates, three polyvinyl siloxanes, and one polyether and gelatin were used. The impression-material/mandibular tissue blocks were processed routinely. Polyvinyl siloxanes were incompatible with embedding resin; alginates, polyether and gelatin could be fixed, decalcified, embedded, and sectioned. Alginates and gelatin could be stained. Success in imaging the tooth crown varied with the preparation, but the alginates, polyether, and gelatin permitted a useful degree of measurement of exposed crown and enamel thickness, along with other morphometric parameters such as thickness of the dentin, lateral mandibular ramus, rete pegs, height of the gingiva, and volume density of vessels and inflammatory cells in the lamina propria. In conclusion, this new application for impression materials allows gingival coverage of tooth crown, as well as numerous other parameters to be measured for comparison with clinical data.

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