ARYL-HYDROCARBON RECEPTOR FUNCTION IN EARLY VERTEBRATES - INDUCIBILITY OF CYTOCHROME-P450 1A IN AGNATHAN AND ELASMOBRANCH FISH

The mammalian aryl hydrocarbon receptor (AHR) is a ligand-activated tr anscription factor that controls the expression of cytochrome P450 1A (CYP1A) genes in response to halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The natural ligand and no rmal physiologic function of this protein are as yet unknown. One appr oach to understanding AHR function and significance is to determine th e evolutionary history of this receptor and of processes such as CYP1A induction that are controlled by the AHR in mammals. In these studies , AHR function was evaluated in representative cartilaginous fish (lit tle skate, Raja erinacea) and jawless fish (sea lamprey, Petromyzon ma rinus and Atlantic hagfish, Myxine glutinosa), using CYP1A induction a s a model AHR-dependent response. Treatment of skate with beta-naphtho flavone (BNF) caused an 8-fold increase in hepatic ethoxyresorufin O-d eethylase (EROD) activity as well as a 37-fold increase in the content of immunodetectable CYP1A protein. Evidence of CYP1A inducibility was also obtained for another cartilaginous fish, the smooth dogfish Must elus canis. In contrast, hepatic EROD activity was not detected in unt reated lamprey nor in lamprey treated with 3,3',4,4'-tetrachlorobiphen yl (TCB), a potent AHR agonist in teleosts. A possible CYP1A homolog w as detected in lamprey hepatic microsomes by one of three antibodies t o teleost CYP1A, but expression of this protein was not altered by TCB treatment. CYP1A protein and catalytic activity were measurable in ha gfish, but neither was induced after treatment with TCB. These results suggest that the AHR-CYP1A signal transduction pathway is highly cons erved in gnathostomes, but that there may be fundamental differences i n AHR signaling or AHR-CYP1A coupling in agnathan fish. Agnathan fish such as hagfish and lamprey may be interesting model species for exami ning possible ancestral AHR functions not related to CYP1A regulation. (C) 1998 Elsevier Science Inc. All rights reserved.