The adaptive response to 3‐methylcholanthrene is altered in the liver of adrenalectomized rats

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand‐activated transcription factor that mediates most effects of aromatic hydrocarbons, such as 3‐methylcholanthrene (MC). The in vivo regulation of hepatic AHR and whether changes in AHR levels affect the response to agonists are not fully understood. We discovered that the level of hepatic AHR protein was decreased in male adrenalectomized (ADX) rats 4 days after surgery. We studied the consequences of this AHR depletion by measuring expression of aromatic hydrocarbon‐responsive genes in the liver of MC‐treated ADX and SHAM‐operated rats at 6 and 54 h post‐MC. Hepatic AHR protein was depleted in ADX rats at 4 days, but not 6 days, post‐surgery. At this later time point, MC increased hepatic AHR protein in ADX but not SHAM rats. Hepatic cytochrome P450 1A1 (CYP1A1), AHR and P450 reductase (CYPRED) mRNA was induced by MC to a greater extent in SHAM versus ADX rats at 6 h. At 54 h post‐MC, induction by MC was greater in ADX versus SHAM rats for CYP1A1 and CYPRED mRNA. CYP1A1 protein levels corresponded to its mRNA. These results suggest that the adaptive response to MC in liver of ADX rats is impaired at 6 h but sustained and enhanced at 54 h relative to SHAM. Changes in the level of hepatic AHR caused by ADX affect the magnitude and duration of the response to aromatic hydrocarbons in vivo in a gene‐dependent manner. [Support: CIHR; OGS; U of Toronto; Peterborough K.M. Hunter Studentship]