Toxicological implications of polymorphisms in receptors for xenobiotic chemicals: the case of the aryl hydrocarbon receptor.
Mechanistic toxicology has predominantly been focused on adverse effects that are caused by reactive metabolites or by reactive oxygen species. However, many important xenobiotics exert their toxicity, not by generating reactive products, but rather by altering expression of specific genes. In particular, some environmental contaminants target nuclear receptors that function as regulators of transcription. For example, binding of xenobiotic chemicals to steroid receptors is a principle mechanism of endocrine disruption. The aryl hydrocarbon receptor (AHR) mediates toxicity of dioxin-like compounds. In mice, a polymorphism in the AHR ligand-binding domain reduces binding affinity by about 10-fold in the DBA/2 strain compared with the C57BL/6 strain; consequently, dose-response curves for numerous biochemical and toxic effects are shifted about one log to the right in DBA/2 mice. In the Han/Wistar (Kuopio) (H/W) rat strain, a polymorphism causes a deletion of 38 or 43 amino acids from the AHR transactivation domain. This deletion is associated with a greater than 1000-fold resistance to lethality from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Genes in the conventional AH gene battery (e.g. CYP1A1, CYP1A2, CYP1B1, ALDH3A1, NQO1 and UGT1A1) remain responsive to TCDD in H/W rats despite the large deletion. However, the deletion may selectively alter the receptor's ability to dysregulate specific genes that are key to dioxin toxicity. We are identifying these genes using an expression array approach in dioxin-sensitive vs. dioxin-resistant rat strains and lines. Polymorphisms exist in the human AH receptor, but thus far they have not been shown to have any substantial effect on human responses to AHR-ligands.
Okey
Allan B
AB
Department of Pharmacology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada. allan.okey@utoronto.ca
Franc
Monique A
MA
Moffat
Ivy D
ID
Tijet
Nathalie
N
Boutros
Paul C
PC
Korkalainen
Merja
M
Tuomisto
Jouko
J
Pohjanvirta
Raimo
R
D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D011110:Polymorphism, Genetic; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000502:physiology; D015262:Xenobiotics / Q000633:toxicity*
D018336:Receptors, Aryl Hydrocarbon; D015262:Xenobiotics