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Drug metabolism and disposition: the biological fate of chemicals

The aryl hydrocarbon receptor pathway and the response to 3-methylcholanthrene are altered in the liver of adrenalectomized rats.


PMID 20881032

Abstract

The aryl hydrocarbon receptor (AHR) is activated by 3-methylcholanthrene (MC), a polycyclic aromatic hydrocarbon, and environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Adrenalectomized (ADX) rats have decreased hepatic AHR protein and lower levels of MC-induced CYP1B1 mRNA. To further characterize the effects of decreased AHR protein and the response to MC in ADX rats, we measured AHR-mediated responses in the liver of sham-operated (SHAM) and ADX rats, 6 and 54 h after MC treatment. CYP1A2 mRNA was suppressed by 46 to 60% 4 days after ADX in vehicle-treated animals. AHR mRNA was induced 4-fold 6 h after MC in SHAM rats, but no induction was observed in ADX rats. The MC-induced 7-ethoxyresorufin O-deethylation (EROD) activity in ADX rats was 35% of the activity in the MC-treated SHAM group at 6 h. At 54 h after treatment, the induction of EROD activity by MC was more pronounced in ADX rats than at 6 h. To assess the overall capacity for hepatic P450-mediated metabolism, we measured NADPH-cytochrome P450 oxidoreductase (POR) activity. POR activity was decreased by 50% after ADX. We have shown that the response to MC in ADX rats is suppressed for some, but not all, AHR-mediated responses and that reduced POR activity after ADX could contribute to a decreased capacity for P450-dependent metabolism. The current study contributes to our understanding of how adrenal-dependent factors modulate the AHR pathway and the response to MC in vivo.

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