The 2001 Veylien Henderson Award of the Society of Toxicology of Canada. Positive and negative transcriptional regulation of cytochromes P450 by polycyclic aromatic hydrocarbons.
Most responses to aromatic hydrocarbons such as 3-methylcholanthrene (MC) and 2,3,7,8-tetrachlorodibenzo-p-dioxin are mediated by the aromatic hydrocarbon receptor (AHR). The AHR regulates induction of drug-metabolizing enzymes such as cytochrome P450 1A1. However, the expression of several genes of biological significance is decreased by these chemicals. We are examining the mechanisms by which aromatic hydrocarbons suppress constitutive hepatic cytochromes P450, especially the male-specific rat liver cytochrome P450 2C11 (CYP2C11), which is regulated by pulsatile growth hormone (GH) secretion. Aromatic hydrocarbons suppress CYP2C11 via a transcriptional mechanism both in vivo and in cultured hepatocytes, and the AHR appears to be involved; however, studies of protein-DNA interactions and reporter genes driven by the CYP2C11 5'-flanking region have not provided a definitive mechanism for this response. MC attenuates the ability of GH to stimulate hepatic CYP2C11 expression in hypophysectomized (hypx) male rats, and this prompted studies of effects of aromatic hydrocarbons on hepatic GH signaling pathways as a novel aspect of endocrine disruption. Our studies with hypx rats also suggest that the hepatic AHR protein is regulated by a pituitary factor(s). The goal of these molecular mechanistic studies is to improve our understanding of how environmental contaminants modulate the expression of genes coding for xenobiotic- and hormone-metabolizing enzymes.
Riddick
David S
DS
Department of Pharmacology, Medical Sciences Building, University of Toronto, Toronto, ON M5S 1A8, Canada. david.riddick@utoronto.ca
Lee
Chunja
C
Bhathena
Anahita
A
Timsit
Yoav E
YE
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001363:Awards and Prizes; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004785:Environmental Pollutants / Q000633:toxicity*; D005786:Gene Expression Regulation; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010902:Pituitary Gland / Q000502:physiology; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D039181:Steroid 16-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D004785:Environmental Pollutants; D006841:Hydrocarbons, Aromatic; D018336:Receptors, Aryl Hydrocarbon; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D019363:Cytochrome P-450 CYP1A1; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase