Impact of Cyp1a2 or Ahr gene knockout in mice: implications for biomonitoring studies.
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) 10mg/kg, benzo(a)pyrene (BaP) 33.3mg/kg or dibenzo(c,g)carbazole (DBC) 8 mg/kg, and sacrificed after 24h. DNA from livers, skin and/or urinary bladders were isolated and (32)P-post labelled.


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.
Talaska
Glenn
G
The Department of Environmental Health, The University of Cincinnati School of Medicine, 3223 Eden Ave, Cincinnati, OH 45267-0056, USA. Glenn.Talaska@UC.edu
Ginsburg
David
D
LaDow
Kathy
K
Puga
Alvaro
A
Dalton
Timothy
T
Warshawsky
David
D
D000611:Aminobiphenyl Compounds / Q000633:toxicity; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene / Q000633:toxicity; D002227:Carbazoles / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D019388:Cytochrome P-450 CYP1A2 / Q000172:deficiency / Q000235:genetics*; D018736:DNA Adducts; D004784:Environmental Monitoring; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics*; D012867:Skin / Q000187:drug effects / Q000378:metabolism
D000611:Aminobiphenyl Compounds; D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D002227:Carbazoles; D002273:Carcinogens; D019388:Cytochrome P-450 CYP1A2; D018736:DNA Adducts; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse; C006757:4-biphenylamine; C013478:7H-dibenzo(c,g)carbazole