enzymes. This interrelationship between different enzymes and substrates can be

illustrated by the metabolism of P-estradiol in humans, which can be biotransformed both

via sulfonation (SULTIE1, which also acts on 7-hydroxymethyl-12-dimethylbenz-

anthracene, the product of CYP450-catalyzed hydroxylation of 7, 12-dimethyldibenz-

anthracene (Glatt et al., 1995)) and glucuronidation (UGTIA1, which can also conjugate

1-naphthol (Radominska-Pandya et al., 1999)).

 While these enzymes mainly represent a cellular defense mechanism against

toxicity, occasionally procarcinogenic and protoxic xenobiotics are metabolized to active

metabolites that attack macromolecules such as DNA, proteins and lipids.

 In exposed organisms, metabolism is an important factor in determining the

bioaccumulation, fate, toxicokinetics, and toxicity of contaminants. The majority of the

compounds of interest to this study are derived from Phase I metabolism of

environmental pollutants. These metabolites have been shown to have toxic effects both

in vitro and in vivo, effects that can be eliminated by Phase II biotransformation (Chapter

2). In addition, contaminant exposure can result in the induction or inhibition of both

Phase I and Phase II enzymes. For example, induction of CYP 1A (e.g., by polyaromatic

hydrocarbons (PAHs) or co-planar polychlorinated biphenyls (PCBs)), CYP 2B and

CYP3A (e.g., by o-chlorine substituted PCBs) will lead to increased formation of

hydroxylated metabolites. Thus, a balance between the CYP and conjugative Phase II

enzymes, sometimes directly mediated by the xenobiotic substrates and/or their

metabolites, is responsible for either the detoxification or the accumulation of toxic

metabolites in the body. The final removal of these metabolites from the cell is brought

about by several different groups of membrane proteins (e.g., organic anion transport