Phase I Reactions

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Monooxygenations of xenobiotics are the major type of Phase I reaction. They are also called mixed-function oxidations. One atom of a molecule of oxygen is accepted by the substrate while the other oxygen atom is reduced to water. A summary of this process is shown here:

There are two different classes of enzymes which belong to the category of monooxy-genases (or mixed function oxidases, also called microsomal oxygenases) and, therefore, carry out the process depicted here. The cytochrome P450 system is the larger of the two categories and actually is composed of over 400 different enzymes, all of which carry out the general reaction indicated above. These reactions are basically similar in the role played by molecular oxygen and the movement of electrons, but substrates and products come from different chemical classes. A multiplicity of enzyme reactions are possible; some of which are shown below:

Enzyme

Epoxidation, hydroxylation

N-,O-,S-dealkylation

N-,S-,P-oxidation

Desulfuration

Dehalogenation

Some Known Substrates

Aldrin, benzo alpha-pyrene Methylmercaptan, atrazine Chlorpromazine Parathion

Carbon tetrachloride, chloroform

Details of some of these reactions are illustrated in the reaction outlines shown below (Figures 6.1-6.3).

The ultimate carcinogen in tobacco smoke is benzo (alpha) pyrene 7,8-diol-9,10-epoxide. Its formation by a Phase 1 reaction is shown here (Figure 6.2).

Biotransformation, whether completed by the P450 system or some other biotrans-forming enzyme is rarely a simple process. A single metabolic transformation does not usually occur but, instead, a xenobiotic is subject to several different processes

Hydroxylation:

Dealkylation:

Deamination: R NH2

R NHOH

Reduction of carbonyls:

II O

Epoxide formation:

FIGURE 6.1 Some Phase 1 reactions that occur in biotransformation.

concurrently. An example is the metabolism of chlorpromazine (Figure 6.3). Which specific metabolic products form is related to the enzymes that are present. It is usually also dependent to some extent on the concentration of the xenobiotic.

Site of Biotransformation

The major organ that carries out Phase I conversions is the liver and the major site within the liver is the endoplasmic reticulum of the liver cell. Because components of the endoplasmic reticulum appear in the microsomal fraction when cell homoge-nates are separated into fractions by ultracentrifugation, these cytochrome P450 enzymes are also called microsomal oxygenases. Although most microsomal oxy-genase activity occurs in the liver, the distribution of these enzymes is extensive. Other organs which contain them, in approximate descending order of enzyme activity, are lungs, kidney, adrenal cortex, gut, spleen, heart, and muscle.

Flavin-Containing Monooxygenase

The second kind of monooxygenase enzymes is known as the flavin-containing monooxygenases (Figure 6.4). This is a much smaller group than the P450 system, but it has the same basic reaction mechanism and is dependent on NADPH and molecular oxygen. Flavin monooxygenases catalyze the breakdown of secondary

Benzo-a-pyrene

Benzo(a)pyrene epoxide

Benzo(a)pyrene 7,8 diol-9,10 epoxides

FIGURE 6.2 Biotransformation of benzo (a) pyrene to carcinogenic products.

Biotransformation Chlorpromazine

Didesmethylchlorpromazine

FIGURE 6.3 Variety of reactions involved in chlorpromazine metabolism. © 2002 by CRC Press LLC

Didesmethylchlorpromazine

FIGURE 6.3 Variety of reactions involved in chlorpromazine metabolism. © 2002 by CRC Press LLC

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