Strain differences in cytochrome P4501A1 gene expression caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat liver: role of the aryl hydrocarbon receptor and its nuclear translocator.

Rat strain variation in hepatic cytochrome P4501A1 (CYP1A1) gene expression caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated along with possible underlying mechanism. TCDD at a single oral dose of 13.5 ng/kg body weight significantly increased hepatic CYP1A1 mRNA expression in DRH, Long-Evans Cinamon (LEC), Long-Evans (LE), and Holtzman (HO) rats, but not in Sprague-Dawley (SD), Wistar-Imamichi (WI), Lewis (LEW), and Fisher-344 (F344) strains. All showed significant induction of CYP1A1 mRNA at a dose of 40 ng/kg, the relative levels decreasing in the order DRH, LEC, HO, LE, F344, WI, LEW, and SD. A more than 35-fold difference in the induction of CYP1A1 RNA was evident between the DRH and SD strains. Based on CYP1A1 induction, classification into two distinctly separate groups was possible, high responders (DRH, LEC, HO, and LE) and low responders (SD, LEW, WI, and F344). The expression levels closely correlated with the steady-state aryl hydrocarbon receptor (AhR) mRNA expression, this being approximately four-fold higher in the high than in the low responder group. Analysis of the aryl hydrocarbon receptor nuclear translocator (ARNT) showed the presence of a wild type as well as an alternately spliced variant in all strains, with a 45-bp deletion whose sequence corresponded to part of 5' end of the basic region of the basic helix-loop-helix domain. Expressed levels of both products were almost equal in all the strains except DRH, LEC and HO, where the wild form predominated. The results suggest that differential expression of both AhR and ARNT are responsible for rat strain-specific differences in TCDD induced CYP1A1 expression.