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NATURE AND STABILITY OF REACTIVE METABOLITES

151

Table 8.1 Enzymes Important in Catalyzing Met-

 

abolic Activation Reactions

 

 

 

 

 

Type of Reaction

Enzyme

 

 

 

 

 

Oxidation

Cytochrome P450s

 

 

Prostaglandin synthetase

 

 

Flavin-containingmonooxygenases

 

 

Alcohol and aldehyde

 

 

dehydrogenases

 

Reduction

Reductases

 

 

Cytochromes P450

 

 

Gut microflora

 

Conjugation

Glutathione transferases

 

 

Sulfotransferases

 

 

Glucuronidases

 

Deconjugation

Cysteine S-conjugateβ-lyase

 

Hydrolysis

Gut microflora, hydrolyses

 

 

 

 

 

microflora may also lead to the formation of reactive toxic products. With some chemicals only one enzymatic reaction is involved, whereas with other compounds, several reactions, often involving multiple pathways, are necessary for the production of the ultimate reactive metabolite.

8.3NATURE AND STABILITY OF REACTIVE METABOLITES

Reactive metabolites include such diverse groups as epoxides, quinones, free radicals, reactive oxygen species, and unstable conjugates. Figure 8.2 gives some examples of activation reactions, the reactive metabolites formed, and the enzymes catalyzing their bioactivation.

As a result of their high reactivity, reactive metabolites are often considered to be short-lived.This is not always true, however, because reactive intermediates can be transported from one tissue to another, where they may exert their deleterious effects. Thus reactive intermediates can be divided into several categories depending on theirhalf-lifeunder physiological conditions and how far they may be transported from the site of activation.

8.3.1Ultra-short-livedMetabolites

These are metabolites that bind primarily to the parent enzyme. This category includes substrates that form enzyme-boundintermediates that react with the active site of the enzyme. Such chemicals are known as “suicide substrates.” A number of compounds are known to react in this manner with CYP, and such compounds are often used experimentally as CYP inhibitors (see the discussion of piperonyl butoxide, Section 7.2.2). Other compounds, although not true suicide substrates, produce reactive metabolites that bind primarily to the activating enzyme or adjacent proteins altering the function of the protein.

152

REACTIVE METABOLITES

 

 

 

 

 

 

 

 

 

CH3CH2O

S

 

 

 

 

 

 

 

O

 

 

Detoxication

P

 

NO

 

 

 

CH3CH2O

 

 

 

O

2

P450

P O

 

NO2

CH3CH2O

 

 

 

 

 

CH3CH2O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Inhibits

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Parathion

 

 

 

 

Paraoxon

 

 

 

Acetylcholinesterase

 

 

 

H

 

 

 

H

 

H

 

 

O

 

 

 

 

 

 

 

 

 

 

 

H

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

P450

 

 

 

 

 

 

 

 

 

 

 

 

 

H

 

Cl

 

H

 

 

 

H2C

Cl

 

 

 

 

 

Cl

 

 

 

 

 

 

O

 

 

H

 

 

 

 

 

 

 

 

 

 

 

 

 

Vinyl chloride

 

Chloroethylene oxide

 

Chloroacetaldehyde

 

 

 

 

 

 

 

Covalent binding to

 

GSH conjugation

 

 

 

 

 

 

 

macromolecules

 

 

 

 

 

 

CH3OH

Alcohol

 

 

HCHO

Aldehyde

HCOOH

 

 

Dehydrogenase

 

 

 

 

 

 

 

 

Dehydrogenase

 

 

 

Methanol

 

 

 

 

Formaldehyde

 

 

Formic acid

 

 

 

 

O

 

 

 

 

 

 

O

 

 

 

 

 

 

O

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

 

P450

 

O

 

 

Detoxication

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

O

 

 

 

 

O

 

O

 

 

 

O

CH3

 

 

 

 

Covalent binding

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

CH3

 

 

 

 

 

 

 

 

 

 

 

to macromolecules

 

Aflatoxin B1 (AFB1)

 

 

 

 

Aflatoxin B1 epoxide

 

Figure 8.2 Examples of some activation reactions.

8.3.2Short-livedMetabolites

These metabolites remain in the cell or travel only to nearby cells. In this case covalent binding is restricted to the cell of origin and to adjacent cells. Many xenobiotics fall into this group and give rise to localized tissue damage occurring at the sites of activation. For example, in the lung, the Clara cells contain high concentrations of CYP and several lung toxicants that require activation often result in damage primarily to Clara cells.

8.3.3Longer-livedMetabolites

These metabolites may be transported to other cells and tissues so that although the site of activation may be the liver, the target site may be in a distant organ. Reactive intermediates may also be transported to other tissues, not in their original form but as conjugates, which then release the reactive intermediate under the specific conditions in the target tissue. For example, carcinogenic aromatic amines are metabolized in the liver to the N -hydroxylatedderivatives that, following glucuronide conjugation, are transported to the bladder, where theN -hydroxyderivative is released under the acidic conditions of urine.