X

Aldehyde Alcohol

Methylenedioxybenzene oxidation

Figure 6.8. Metabolism of oxygen-containing compounds. Ethers. The P450-mediated oxidation of ethers proceeds by oxidation of the alpha carbon via HAT to form a radical, followed by a hydroxyl radical rebound. This mechanism results in the formation of a hemiacetal that hydrolyses to an alcohol and an aldehyde product. Methylenedioxybenzenes. The P450-mediated oxidation of methylenedioxybenzenes proceeds via oxidization of the methylene to a carbene (a carbon with six valence electrons) intermediate. This intermediate coordinates with the heme in the P450 active site and results in inactivation of the P450 enzyme.

Carbene

Figure 6.8. Metabolism of oxygen-containing compounds. Ethers. The P450-mediated oxidation of ethers proceeds by oxidation of the alpha carbon via HAT to form a radical, followed by a hydroxyl radical rebound. This mechanism results in the formation of a hemiacetal that hydrolyses to an alcohol and an aldehyde product. Methylenedioxybenzenes. The P450-mediated oxidation of methylenedioxybenzenes proceeds via oxidization of the methylene to a carbene (a carbon with six valence electrons) intermediate. This intermediate coordinates with the heme in the P450 active site and results in inactivation of the P450 enzyme.

Sulfoxide

Sulfone

R OH

Sulfenic acid

S

R"

Thioether

1

I

Sulfinic acid

W OH

Sulfonic acid

Disulfide

O Thiosulfinate

Thiosulfonate

Figure 6.9. Metabolism of thiols and thioethers. Thioethers are oxidized to S-dealkylation products (including a thiol as one of the products). Both thioethers and thiols can be oxidized to form a number of metabolites. The sulfur can also be oxidized to a sulfoxide or a sulfone.

Pyrrole Epoxidation

Figure 6.10. Pyrrole oxidation. Pyrrole is oxidized via epoxidation, leading to various oxidative metabolites. In the case of 3-methylpyrrole (or 3-methyl-indole), oxidation can proceed via HAT from the methyl group, leading to formation of a 3-methylene-3H-pyrrole intermediate. This intermediate can react with nucleophiles such as GSH to form a stable conjugate.

Figure 6.10. Pyrrole oxidation. Pyrrole is oxidized via epoxidation, leading to various oxidative metabolites. In the case of 3-methylpyrrole (or 3-methyl-indole), oxidation can proceed via HAT from the methyl group, leading to formation of a 3-methylene-3H-pyrrole intermediate. This intermediate can react with nucleophiles such as GSH to form a stable conjugate.

o

A

Furan

reduction or oxidation

Figure 6.11. Furan oxidation. P450-mediated furan oxidation proceeds by epoxidation and leads to formation of a g-ketoenal. This reactive intermediate can be trapped by semicarbazide. It can also rearrange and/or undergo further oxidation or reduction as shown.

Figure 6.11. Furan oxidation. P450-mediated furan oxidation proceeds by epoxidation and leads to formation of a g-ketoenal. This reactive intermediate can be trapped by semicarbazide. It can also rearrange and/or undergo further oxidation or reduction as shown.

H2N NH NH;

y-thionoenal

Nu y-thionoenal

O0

\Ù <YN

H

\ Nu

Nu

Figure 6.12. Thiophene oxidation. The three proposed mechanisms of thiophene oxidation are: epoxidation, S-oxide formation, and S-Cl formation (no direct evidence of an S-Cl intermediate). Semicarbazide traps the epoxide intermediate to form pyridazine, which suggests the formation of a g-thioenal intermediate. Thiophenes can also rearrange and/or be oxidized or reduced to various stable metabolites.

X

^—N

X=N, O, S

X

< N

X=O, S

Y=N, C

Onh-

Figure 6.13. Oxidation of imidazole, oxazole, and thioazoles. Oxidation of 1,3 analogs can lead to a number of oxidative metabolites that include open ring systems. The 1,2 analogs can be reduced to form an open ring by enzymes such as AO (see Chap. 2).

f r*!i!rVxCO2H

co2h nh2

CO2H

CO2H

Figure 6.14. Pyridine oxidation. Besides ring oxidation, similar to aromatic ring oxidation (see Sect. 6.6.2), the nitrogen can also be oxidized to form N-oxide or N-methylated products. Multistep oxidations and reductions can produce an open ring product. Here, we present a few examples, but many more have been reported after undergoing reactions with microbes under anaerobic and aerobic conditions (Kaiser et al. 1996).

Reaction

Biotransformation

A mass

Glucuronidation ll I. R

+ 176.0321

Sulfonation

+79.9568

Acetylation

+42.0106

Methylation

Glycine conjugation

+73.0164

Taurine conjugation

+122.9990

Figure 6.15. Common conjugative reactions.

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Additional Reading

See Chap. 2

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