Humboldt State University ® Department of Chemistry

Richard A. Paselk

Chem 451

Biochemical Toxicology

Spring 2010

Lecture Notes:: 25 February

© R. Paselk 2008
 
     
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Toxicant Metabolism

The general strategy among organisms is to eliminate toxics, so the major biotransformations increase solubility in water, and therefore aid in elimination.

Two major types of reactions:

  1. Phase One Reactions: generally oxidations to provide a reactive polar group on the molecule.
  2. Phase Two Reactions: conjugate a highly soluble moiety onto a reactive polar group. Increases solubility and often switchs to biliary excretion.

Phase One Reactions

Most phase one reactions are catalyzed by the microsomal monooxygenases (mixed function oxidases). These enzymes are localized to a large degree on the sER, though they are also found on the rER. The most common microsomal oxidases are the P450s, a large family of enzymes catalyzing the same chemistry on a wide variety of mostly non-polar substrates. Different forms of the enzyme may be induced by exposure to different chemicals. Thus exposure to phenobarbital or PBB's result in P450s with different specificities, though they catalyze the same reaction. Over a dozen families of P450 are known which catalyze the hydroxylation/epoxidation of endogenous and/or exogenous compounds. The overall reaction can be summarized as:

A generalized electron transport system for the P450 mixed-function oxidases is shown below:

Note the involvement of two reducing agents (the substrate and NAD()PH) to provide the total of four electrons requied by molecular oxygen. We will look at the generalized enzyme mechanism for P450, which is shown in your text in Figure 4.2 on p79, later.

The Table below summarizes some of the common reactions catalyzed by P450 and illustrates the hydroxyl intermediate theme commonly occurring in these reactions.

Common Cytochrome P450 Catalyzed Reactions
Aromatic hydroxylation
Aliphatic hydroxylation  
N-Dealkylation  
O-Dealkylation  
Deamination
N-Oxidation
Sulphoxidation

The mechanism for hydroxylations involving an epoxide intermediate is explained via the so-called NIH-shift, as illustrated for 1-napthol (the same mechanism will also yield 2-napthol - try it):

 

This mechanism is shown in Figure 4.5, p 84 of Timbrell, leading to both posssible positions for the hydroxyl group.

Phase One Monooxygenases: Example Reactions

Epoxidation and Hydroxylation Reactions:

Aromatic Reactions:

chemical equation for the transformation of aldrin to dieldrin

chemical equations for the

chemical structure diagram of the trans-epoxide of benzopyrene

chemical equation for the metabolism of napthol via an epoxide  to 1-napthol and 2-napthol

 


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