History of Biomarkers - Ecological Biomarkers: Indicators of Ecotoxicological Effects - page 18

This reaction constitutes the first phase (phase I) of the biotransformation of organic
compounds that causes hydrophobic compounds to become more water soluble.
The de novo synthesis of P450 proteins by organisms termed as “induction” leads to
increased enzymatic activity. Induction has been well known for 40 years in humans and
other mammals, more recently in fish and plants, and of late in invertebrates (Stegeman
and Hahn 1994). The induction of cytochrome P450 isoenzymes responds to exposure to
xenobiotics by way of a selective, receptor-mediated stimulation of the CYP1A gene tran-
scription rate, resulting in increased levels of specific mRNA, new synthesis of cytochrome
P450 isoenzymes, and an increase in their catalytic activities (e.g., EROD for CYP1A). The
receptor that mediates the regulation of the CYP1A gene expression is known as the AH
(aryl hydrocarbon) receptor (AHR) (Poland and Glover 1975; Guengerich 1993). Studies
have demonstrated that activation of the AHR pathway is necessary for benzo[ a ]pyrene
(B[ a ]P)-induced hepatic carcinogenicity in mice (Shimizu et al. 2000), and 2,3,7,8-tetrachlo-
rodibenzo- p -dioxin (TCDD) and polychlorobiphenyl (PCB) induced early life stage toxici-
ties in fish (Antkiewicz et al. 2006). The functioning of the AHR pathway in fishes is almost
identical to that in mammals, except that fish have two or more forms of AHR (AHR1 and
AHR2) due to genome duplication events (Hahn 2002). After diffusing into the cell, the
xenobiotic binds to a protein complex in the cytoplasm consisting of AHR, a dimer of heat-
shock protein 90 (Hsp90), p23, and ZAP2 (also known as ARA9 and AIP) (Figure 2.1). Upon
ligand binding, ZAP2 is released, exposing the nuclear localization signal on AHR and

Ligand (TCDD, PCB, or PAHs)

ZAP2

AHR

p23

Hsp90
Hsp90

Cytoplasm

ZAP2

AHR

p23

Hsp90

Cyp1a1 Hsp90

(Protein)

Nucleus

AHR

Hsp90

Hsp90 Cyp1a1

ARNT
AHR
XRE

mRNA

Cyp1a

Promote Cyp1a1

ARNT

ARNT

AHRR

AHRR

mRNA

AHRR
ARNT

XRE

FIGURE 2.1
Functioning of the AHR (aryl hydrocarbon receptor) pathway in fishes. After diffusing into the cell, the xenobi-
otic binds to a protein complex in the cytoplasm consisting of AHR, Hsp90, p23, and ZAP2. Upon ligand bind-
ing, ZAP2 is released leading to translocation of AHR from the cytoplasm to the nucleus. Within the nucleus,
Hsp90s are released, and AHR heterodimerizes with the Aryl Receptor Nuclear Translocator (ARNT). The
AHR-ARNT complex then binds to multiple enhancer elements in the promoter region of responsive genes in
the AHR battery such as CYP1A. (From Figure 8.2 of Roméo, M., Wirgin, I.I., in C. Amiard-Triquet, P.S. Rainbow,
and M. Roméo, Tolerance to Environmental Contaminants , CRC Press, Boca Raton, 175-208, 2011. With permission.)