| Chem 451 |
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Spring 2010 |
| Lecture Notes:: 25 February |
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| PREVIOUS |
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:
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.
| 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.
Aromatic Reactions:
- Stable epoxide intermediate - transformation of Aldrin to Dieldrin.
- Epoxides also serve as intermediates -transformation of naphthalene to naphthol. In addition to the products shown below the 1,2-dihydroxy- and 1,2-dihydroxy-1,2-dihydro- napthols are also formed.
- Can get metabolic activation, such as seen in benzopyrenes where the epoxide is a potent carcinogen (note that the epoxide can be cis or trans to the adjacent hydroxyl group, the trans isomer is shown):
- Benzene gives a variety of products:
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Last modified 25 February 2010
© RA Paselk 2001
