A Mechanistic Model of Effects of Dioxin on Gene Expression in the Rat Liver

摘要: Abstract Improved methods for estimating the shape of response curve effects exposure to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) are needed in order evaluate possible adverse health TCDD. A mathematical model has been constructed describe TCDD-mediated alterations hepatic proteins rat. In this it was assumed that TCDD mediates increases liver concentration transforming growth factor-α (TGF-α) by a mechanism which requires aryl hydrocarbon (Ah) receptor. TGF-α subsequently binds epidermal factor (EGF) receptor, process is known cause internalization receptor hepatocytes. This action thought be an early event generation mitogenic signal. Because decreases binding EGF livers intact female rats but not ovariectomized rats, effect further dependent on estrogen action. The postulates Ah receptor-dependent cytochrome P450 1A2 (CYP1A2), involved metabolism estradiol, and also incorporates information induction 1A1 (CYP1A1) biochemical curves all these were hyperbolic (Hill exponents equations their expression found 1), indicating proportional relationship between target tissue dose protein at low administered doses successfully reproduced observed distribution TCDD, concentrations CYP1A1 CYP1A2, Ah, estrogen, receptors over wide range.