Glycine N-Methyltransferase Is an Example of Functional Diversity

Abstract

Polycyclic aromatic hydrocarbons such as B[a]P 1 , 3-methylcholanthrene, and TCDD are environmental pollutants that elicit a variety of toxic, teratogenic, and carcinogenic responses in exposed animals (1-7). In addition, these substances are potent inducers of certain biotransformation reactions that are catalyzed by the cytochrome P-450-dependent monooxygenases, a super family of isozymic hemoproteins comprising more than 12 gene groups (8). These isozymes display broad substrate specificity and metabolize both endogenous substrates and xenobiotics to electrophilic derivatives, some of which can interact with DNA, thereby potentially activating protooncogenes or inactivating tumor suppressor genes.A principal cytochrome P-450 induced by B[a]P, 3-methylcholanthrene, or TCDD is CYP1A1, which is in part responsible for the activation of PAHs to carcinogenic intermediates. This induction is mediated by receptors, such as the Ah receptor (or dioxin receptor, 8 S protein). The Ah receptor-mediated mechanism is the best characterized and most widely accepted model for PAH-induced expression of CYP1A1 (9, 10). Upon ligand binding, the Ah receptor undergoes a temperature-dependent transformation accompanied by translocation into the nucleus where the ligand receptor complex binds to specific cis-elements (also known as XREs and DREs) present in the 5Ј-regulatory regions of CYP1A1 and of several other genes in the Ah gene battery. The result of such interaction is the transcriptional activation of Ah responsive genes (3,5,6,11). The Ah receptor contains a 95-kDa helix-loop-helix motif, characteristic of several transcriptional activators (12, 13). The mechanism as outlined is more complicated because functional Ah receptor represents a heterodimer that contains, in addition to the ligand binding moiety, a second helix-loop-helix 84-kDa protein component, known as ARNT, which is needed for the nuclear translocation of the ligand-receptor complex (14 -16). In addition, heat shock protein 90 plays an important role in the intracellular localization of the Ah receptor (see review in Ref. 42).Evidence has been published suggesting that the induction of rat CYP1A1 after treatment with PAHs, such as B[a]P or B[e]P, may require an Ah receptor-independent pathway mediated by another cytosolic receptor protein, the 4 S PAHbinding protein (17)(18)(19)(20)(21)(22)(23). Both the Ah receptor and 4 S PAHbinding protein exhibit distinct ligand binding specificities, with 3-methylcholanthrene interacting with both. B[a]P and B[e]P have been demonstrated to act solely as ligands for the 4 S protein in rat liver and rat hepatoma cells (17, 24 -28). Like the Ah receptor, the 4 S protein undergoes nuclear translocation upon interaction with the PAH (17, 29 -31) and complexes to cis-response elements in different regulatory regions of CYP1A1 (21,32,33).The 4 S protein has been purified to homogeneity using a * This research was supported by National Institutes of Health Grant CA 36105. The costs of publication of this article were defrayed i...

Diacylglycerol effects on phosphatidylinositol‐specific phospholipase C activity and vesicle fusion

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Reduced cytochrome P4501A activity and recovery from oxidative stress during subchronic benzo[a]pyrene and benzo[e]pyrene treatment of rainbow trout

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Benzo(a)pyrene induced glycine N-methyltransferase messenger RNA expression in Fundulus heteroclitus embryos

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