Impact of Cyp1a2 or Ahr gene knockout in mice: Implications for biomonitoring studies

Abstract

Studies of the impact of phase 1 enzyme polymorphisms on genetic damage have yielded mixed results. We studied how genetic damage would be altered when specific genes were ablated under low dose conditions. Methods Knockouts (KO) were generated from c57bl6/J mice with mutations in Cyp1a2 or Ahr receptor that eliminated gene product function. Animals were treated topically with either 4-aminobiphenyl (4ABP) 10 mg/kg, benzo(a)pyrene (BaP) 33.3 mg/kg or dibenzo(c,g)carbazole (DBC) 8 mg/kg, and sacrificed after 24 h. DNA from livers, skin and/or urinary bladders were isolated and 32P-postlabelled. Results Cyp1a2−/− mice did not differ in 4ABP DNA adduct levels in either urinary bladder or liver compared to wildtype. There was a sex difference in the organ affected. Cyp1a2 knockout reduced skin BAP adduct levels 50% and AHR knockout reduced skin BAP adduct levels by 90%. There was no impact of either knockout on the levels of DBC-DNA adducts in any tissue. Conclusions Ablation of specific metabolizing enzymes had compound- and tissue-specific effects in mice. Phenotypic variability in single CYP enzymes may have minor impact in humans at low doses, but variation in the ability to induce the family of CYPs may have a greater impact.