Characterization of the dose-response of CYP1B1, CYP1A1, and CYP1A2 in theliver of female Sprague-Dawley rats following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin

One of the current knowledge gaps in the evaluation of risk for human expos ure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the relationship betwe en gene expression induced by TCDD and more complex biological responses su ch as altered growth, differentiation, and neoplasia This study investigate s the dose-dependent expression of CYP1A1, CYP1A2, and CYP1B1 in the livers of female Sprague-Dawley rats chronically exposed to TCDD. Animals were tr eated biweekly for 30 weeks with daily averaged doses of 0 to 125 ng TCDD/k g/day. Immunoblot analysis showed that protein levels for CYP1B1, CYP1A1, a nd CYP1A2 exhibited a dose-dependent induction by TCDD. However, CYP1A1 and CYP1A2 protein levels were approximately 100-fold higher than CYP1B1, whic h could not be detected by either immunoblot analysis or immunohistochemist ry in the livers of rats treated with TCDD for 30 weeks at a dose-equivalen t less than 35.7 ng/kg/day. In control animals, CYP1A1 and CYP1A2 RNA level s, measured by quantitative RT-PCR, were 1100- and 15,000-fold higher than that of CYP1B1, respectively. TCDD induced CYP1B1 RNA levels at all doses, although absolute TCDD-induced levels of CYP1A1 and CYP1A2 at the highest d ose (125 ng/kg/day) were more than 40-fold higher than that of CYP1B1. Whil e the liver concentration of TCDD required for half-maximal induction of CY P1A1, CYP1A2, and CYP1B1 RNA levels was similar, the shaping parameter (Hil l coefficient) of the dose-response curve for CYP1B1 was significantly high er than that for CYP1A1 or CYP1A2. The low level of TCDD-induced CYP1B1 exp ression in the liver relative to that of the CYP1A1 and CYP1A2 suggest that , if CYP1B1 is involved in TCDD-induced hepatocarcinogenesis, its endogenou s function is likely to be unique and not overlapping with that of CYP1A1 o r CYP1A2. (C) 1999 Academic Press.