Peroxidatic oxidation of benzo[a]pyrene and prostaglandin biosynthesis

Abstract

The arachidonic acid dependent oxidation of benzo[a]pyrene to a mixture of 3,6-, 1,6-, and 6,12-quinones has been studied by using enzyme preparations from sheep seminal vesicles. Maximal oxidation is observed at 100 microM benzo[a]pyrene and 150 microM arachidonic acid. The arachidonic acid dependent oxidation is peroxidatic and utilizes prostaglandin G2 (PGG2), generated in situ from arachidonate, as the hydroperoxide substrate. 15-Hydroperoxy-5,8,11,13-eicosatetraenoic acid is equivalent to PGG2 as a hydroperoxide substrate, but hydrogen peroxide, cumene hydroperoxide, and tert-butyl hydroperoxide are much poorer substrates. Arachidonic acid dependent benzo[a]pyrene oxidation by microsomal and solubilized enzyme preparations is markedly.

Decreasing Inhibitory Potency of Prostaglandin Synthetase Inhibitors during Their Cooxidative Metabolism

“…According to Marneit [4], Marnett and Reed [5] and Marnett et al [6], this metabolism is due to the hydroperoxidase rather than the fatty acid cyclooxygenase activity of the enzyme. Because of our studies on a variety of cooxy genation substrates using both PG synthetase and lipoxygenase preparations, we tend to speculate that the crucial cooxygenating step is not the same for all substrates.…”

“…On the other hand, another peroxidative pathway of arachidonic acid generating hydroperoxy fatty acids is catalyzed by lipoxy genases and may be involved during cooxy genation of suitable substrates. The forma tion ofhydroperoxides isessential for the mech anisms of cooxygenation, but it is supposed that also peroxidative reactions are neces sary for the cooxidative metabolism [5,6], Since 1974, when cooxygenation was first described by Marnett et al [7], a vast number of structurally unrelated compounds have been found to undergo cooxygenation [4] during the oxidative metabolism of arachi donic acid catalyzed by PG synthetases. Among these cooxidative substrates there are the pyrazolon derivatives phenylbutazone and aminopyrine, 1,3-diphenylisobenzofuran (DIBF), and as recently shown [8,9], the aminophenol analgesic paracetamol.…”

Oxygenation of benzo[a]pyrene by plant microsomal fractions

“…Studies with liver microsomes [19,20,24] and with sheep seminal vesicles [25,26] have shown that the 1,6-, 3,6-and 6,12-quinones of BP can arise via the easily autoxidizable 6-hydroxy-BP by reactions which do not involve cytochrome P450. This pathway may also exist in plant microsomes because the % distributions of the 3 quinone fractions formed by soybean and pea microsomes were similar to the % distribution observed in the chemical oxidation of BP (see section 2) and to the % distribution reported in [20] for the autoxidation of 6-hydroxy-BP.…”

“…The BP-quinones possess low or zero mutagenicity against microbial [26,29] or mammalian cells [30] although they are cytotoxic [31]. The formation of glutathione conjugates and polymeric metabolites (see above) as well as the enzymatic co-polymerisation of BP-quinones into lignin (unpublished) may further contribute to the detoxification of BP by plant enzymes.…”

Role of cytochrome P-450 and related enzymes in the pulmonary metabolism of xenobiotics.

“…It is the hydroperoxidase activity of the enzyme that is involved with the co-oxidation of xenobiotics. The co-oxidation of BP by prostaglandin synthase was first demonstrated with microsomal preparations from ram seminal vesicles (83,84). The activity depends upon the addition of arachidonic acid to the microsomal incubations.…”