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 expre ssion caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was investi gated 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 significan t induction of CYP1A1 mRNA at a dose of 40 ng/kg, the relative levels decreasing in the order DRH, LEG, HO, LE, F344, WI, LEW, and SD. A mor e than 35-fold difference in the induction of CYP1A1 RNA was evident b etween the DRH and SD strains. Based on CYP1A1 induction, classificati on into two distinctly separate groups was possible, high responders ( DRH, LEG, HO, and LE) and low responders (SD, LEW, WI, and F344). The expression levels closely correlated with the steady-state aryl hydroc arbon receptor (AhR) mRNA expression, this being approximately four-fo ld higher in the high than in the low responder group. Analysis of the aryl hydrocarbon receptor nuclear translocator (ARNT) showed the pres ence of a wild type as well as an alternately spliced variant in all s trains, with a 45-bp deletion whose sequence corresponded to part of 5 ' end of the basic region of the basic helix-loop-helix domain. Expres sed levels of both products were almost equal in all the strains excep t DRH, LEC and HO, where the wild form predominated. The results sugge st that differential expression of both AhR and ARNT are responsible f or rat strain-specific differences in TCDD induced CYP1A1 expression. (C) 1998 Academic Press.