Page 178 - The Toxicology of Fishes

158 The Toxicology of Fishes

TABLE 4.2
CYP Gene Families, Inducers, Inhibitors, and Substrates
P450
Gene Substrates Inducers Inhibitors

CYP1A BaP PAHs (BaP, BNF, 3-MC) 2-Aminoanthracene
Estradiol Elipticine
7-Ethoxyresorufin Retene PCB 77
Dimethyl benzanthracene Fluoranthene
Phenacetin Dioxins/furans (TCDD) Cadmium
Tributyltin
PCBs (CB77, 126, 169) α-Naphthoflavone
Parathion
Ketoconazole
Miconazole
Clotrimazole
SKF525A
CYP1B Estradiol (?) BaP, TCDD ?
CYP1C ? BaP, TCDD ?
CYP2K1 Lauric acid (ω−1) Diethyldithiocarbamate (activator) Ketoconazole
BNF (decrease) Miconazole
Aflatoxin B 1
17β-Estradiol Testosterone (decrease mRNA) Clotrimazole
Benzphetamine Estrogens (decrease protein) Cimetidine
Progesterone (16α) Parathion
α-Naphthoflavone
CYP2M1 Lauric acid Estrogens (decrease protein) ?
(ω−6)
Progesterone
CYP2N1 Arachidonic acid TPA/starvation (decrease mRNA) ?
Benzphetamine
Alkoxyresorufins
CYP2N2 Arachidonic acid TPA/starvation (decrease mRNA) ?
Benzphetamine
Alkoxyresorufins
CYP2P1 — Fasting/refeed (increase mRNA) ?

NADPH–cytochrome P450 reductase or NADH–cytochrome b reductase. The next step involves cleav-
5
age of the oxygen–oxygen bond, uptake of two protons, and release of water. Oxygen is inserted into
the substrate through generation of hydroxyl and carbon free radicals. Finally, dissociation of ROH
restores the P450 to the initial ferric state (Parkinson, 2001). In addition, the peroxide shunt can allow
a peroxy compound to substitute for oxygen in substrate oxidation.
Expression of CYP genes are regulated by diverse mechanisms. Basal levels of individual CYP mRNAs
and proteins are regulated via transcriptional and post-transcriptional processes, including mRNA and
protein stabilization or degradation. Induction of CYP gene expression of isozymes in families one
through three has been extensively investigated in vertebrates, including fish, and is described in the
next sections of this chapter. Table 4.2 summarizes many inducers, inhibitors, and substrates of CYP1,
CYP2, and CYP3 which can be used to measure induction of specific CYP isozyme-dependent activities
in fish research. As shown in the table, many inducers, such as PAHs, are substrates for the CYPs that
they induce and therefore stimulate their own metabolism. CYP-mediated metabolism of some substrates
can be highly complex and is dependent on both the species and tissue or organ investigated. Figure 4.3
illustrates many of the oxidative metabolites of BaP that are catalyzed by CYP isoenzymes. The
metabolite profiles are variable and dependent on species differences in expression of CYP isoforms
and their catalytic activities; for example, fish (such as the brown bullhead) treated with BaP preferentially
metabolize the hydrocarbon to the more toxic 7,8- and 9,10-oxidation products (Willett et al., 2000). In
contrast, mussels exposed to BaP preferentially (47% total metabolites) form 1–6, 3–6, and 6–12 BaP
quinones (Michel et al., 1995).