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

Toxicol Appl Pharmacol. 1999 Feb 1;154(3):279-86. doi: 10.1006/taap.1998.8595.

Abstract

One of the current knowledge gaps in the evaluation of risk for human exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the relationship between gene expression induced by TCDDmore complex biological responses such as altered growth, differentiation, and neoplasia. This study investigates the dose-dependent expression of CYP1A1, CYP1A2,CYP1B1 in the livers of female Sprague-Dawley rats chronically exposed to TCDD. Animals were treated biweekly for 30 weeks with daily averaged doses of 0 to 125 ng TCDD/kg/day. Immunoblot analysis showed that protein levels for CYP1B1, CYP1A1, CYP1A2 exhibited a dose-dependent induction by TCDD. However, CYP1A1 and CYP1A2 protein levels were approximately 100-fold higher than CYP1B1, which could not be detected by either immunoblot analysis or immunohistochemistry in the livers of rats treated with TCDD for 30 weeks at a dose-equivalent less than 35.7 ng/kg/day. In control animals, CYP1A1CYP1A2 RNA levels, measured by quantitative RT-PCR, were 1100-15,000-fold higher than that of CYP1B1, respectively. TCDD induced CYP1B1 RNA levels at all doses, although absolute TCDD-induced levels of CYP1A1CYP1A2 at the highest dose (125 ng/kg/day) were more than 40-fold higher than that of CYP1B1. While the liver concentration of TCDD required for half-maximal induction of CYP1A1, CYP1A2,CYP1B1 RNA levels was similar, the shaping parameter (Hill coefficient) of the dose-response curve for CYP1B1 was significantly higher than that for CYP1A1 or CYP1A2. The low level of TCDD-induced CYP1B1 expression in the liver relative to that of the CYP1A1CYP1A2 suggest that, if CYP1B1 is involved in TCDD-induced hepatocarcinogenesis, its endogenous function is likely to be uniquenot overlapping with that of CYP1A1 or CYP1A2.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Cytochrome P-450 CYP1A1 / genetics
  • Cytochrome P-450 CYP1A1 / metabolism*
  • Cytochrome P-450 CYP1A2 / genetics
  • Cytochrome P-450 CYP1A2 / metabolism*
  • Cytochrome P-450 CYP1B1
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Induction / drug effects
  • Female
  • Gene Expression Regulation / drug effects
  • Immunoblotting
  • Liver / drug effects
  • Liver / enzymology*
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / enzymology
  • Polychlorinated Dibenzodioxins / toxicity*
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time

Substances

  • Polychlorinated Dibenzodioxins
  • RNA, Messenger
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP1B1 protein, human
  • Cyp1b1 protein, rat
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP1B1