Benzo pyrene glutathione conjugation

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. 

Figure 13.7. Glutathione conjugation to reactive metabolites by GSTs. Ultimate carcinogens such as benzo[a]pyrene 7,8-diol 9,10-epoxide and aflatoxin B1 8,9-epoxide are glutathione-conjugated for detoxification by GSTM1, GSTp, and GST A, respectively. Lipid peroxidation product 4-hydroxy-2-nonenal is preferentially detoxified by GSTA.

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

Hernandez, 0., M. Walker, R. Cox, G.L. Foureman, B. Smith, and J.R. Bend, Regioselectivity and Stereospecificity in the Enzymatic Conjugation of Glutathione with (+) Benzo(a)pyrene... 

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