Benzo pyrene 4,5-oxide, conjugation

Figure 28 Glutathione conjugation reactions of aromatic and OC, P-unsatu-rated carbonyl compounds, benzo[a]pyrene oxide, and ethacrynic acid, respectively.

Figure 7.2 The metabolic activation of benzo[a]pyrene by cytochrome P-450 1A1 to a diol epoxide metabolite, a mutagen. This is believed to be the ultimate carcinogenic metabolite. Other routes of metabolism also catalyzed by cytochrome P-450 give rise to the 9,10, and 4,5 oxides and subsequent metabolites namely phenols, diols, and glutathione conjugates. The reactive site (carbon atom) on the metabolite is indicated.

Armstrong et al.223 have shown that nonenzymatic trans addition of glutathione to synthetic ( + )-(4S,51 )- and (—)-(4R,5S)-benzo [a]pyrene 4,5-oxides (364 and 365) occurs at carbons 4 and 5 to give two diastereomeric pairs of positional isomers to almost equal extents. Correlations of the glutathione conjugates obtained from the 4,5-oxide derived from cytochrome P-450c-catalyzed oxidation of benzo [a] pyrene with those obtained from the syn-... 

The oxidation of naphthalene was one of the earliest examples of an epoxide as an intermediate in aromatic hydroxylation. As shown in Figure 7.3, the epoxide can rearrange nonenzymatically to yield predominantly 1-naphthol, or interact with the enzyme epoxide hydrolase to yield the dihydrodiol, or interact with glutathione S-transferase to yield the glutathione conjugate, which is ultimately metabolized to a mercapturic acid. These reactions are also of importance in the metabolism of other xenobiotics that contain an aromatic nucleus, such as the insecticide carbaryl and the carcinogen benzo(a)pyrene. 

Some of these oxidative metabolites are biologically active and may even be more toxic than their parent compounds. Conversion by conjugation reactions is considered to lead to termination of the toxicity of these compounds and excretion of the non-toxic conjugates.58 Oxidative metabolism of a parent compound can lead to different products which may be excreted at different rates, as has been demonstrated for hydroxylated benzo[a]pyrenes.58... 

Figure 7.53 Benzo[a]pyrene undergoes aromatic oxidation to produce, among other metaboiites, a 4,5-arene oxide. GST coordinates with the epoxide oxygen which weakens the C-O bonds and makes it easier for GSH to attack from the opposite face to open the ring. Transfer of a proton from GSH to the oxygen compietes formation of the detoxified conjugate.This is an example of nucieophiiic substitution by GSH.

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