Arene-oxide metabolites

Boyd and co-workers interest in the properties of arene oxide metabolites has led them to undertake investigations into the synthesis and isomerization of such compounds (e.g., dibenz[ , ]anthracene 3,4-oxide 27, phenanthrene 3,4-oxide 28, triphenylene 1,2-oxide 29, and dibenz[ ,f]anthracene 1,2-oxide 30 (Figure 4)) <2001J(P1)1091>. 

Martz F, Failinger CD, Blake DA. Phenytoin terato-genesis Correlation between embryopathic effect and covalent binding of putative arene oxide metabolite in gestational tissue. J Pharmacol Exp Ther 1977 203 231-9. 

FIGURE 16.5 Metabolism of bromobenzene (1) to a chemically reactive epoxide (arene oxide) metabolite (2) that can then either bind covalently to nearby macro-molecules, be scavenged by glutathione (GSH) (4) and be further metabolized 7), or be converted nonenzymatically or by epoxide hydrolase to stable hydroxylated metabolites 5, 8). 

A number of K-region arene oxides have been detected as intermediates in the metabolism of the corresponding PAHs in liver systems for example, phenanthrene, benz[a]anthracene, pyrene, benzo [a]pyrene, and dibenz(a,h)anthracene. These K-region arene-oxide metabolites were generally only detected by trapping the radiolabeled intermediate. The arene-oxide metabolite 102 obtained from a-naphthoflavone was found to be sufficiently stable with respect to isomerization and resistant to attack by epoxide hydrolase so that it could be isolated and identified spectroscopically. ... 

The term dihydrodiol is widely used in reference to vicinal dihydroxydihydro-derivatives of aromatic hydrocarbons. Although most known and potential benzene oxide or substituted benzene oxide metabolites tend to be quite unstable, a recent study has described the isolation of a relatively stable arene oxide metabolite of 2,2, 5,5 -tetrachlorobiphenyl. Perhaps because of the generally high susceptibility of benzene oxide 1 and many substituted benzene oxides to isomerize to phenols, relatively little has been reported on the kinetics and regiospecificity of their microsomal epoxide hydrolase (EC 3.3.2.3) catalyzed trans hydration to dihydro-... 

Thalidomide has significant teratogenic effects in humans, and it also affects the central and peripheral nervous systems through unknown mechanisms. Evidence of a toxic arene oxide metabolite is unsubstantiated. Thalidomide likely inhibits neutrophil chemotaxis and monocyte phagocytosis, inhibits free radical formation, and alters the ratio of helper and suppressor T-cells. Reduced formation of tissue necrosis factor-a may be at least partially responsible for the antiinflammatory effects of thalidomide. 

GORDON, G.B., SPIELBERG, S.P., BLAKE, D.A. and BALASEIBRAMANIAN, V. (1981) Thalidomide teratogenesis Evidence for a toxic arene oxide metabolite. Proc. Natn. Acad. Sci. USA, 78,2545. 

LENZ, W. (1965) Epidemiology of congenital malformations. Ann. N.Y. Acad. Sci., 123,128. MARTZ, F., FAILINGER, C. and BLAKE, D.A. (1977) Phenytoin teratogenesis correlation between embryopathic effect and covalent binding of a putative arene oxide metabolite in gestational tissue. J.Pharmac. Exp. Ther., 203, 321. 

The isolation of a stable arene oxide metabolite of naphthalene in liver microsomal incubations provided evidence for the CYP- catalyzed epoxidation on the sp carbons on a simple phenyl ring (Scheme 13). Carcinogenesis following exposure to polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene is thought to arise from arene oxide formation. Arene oxides... 

A rearrangement (NIH shift) occurred during the transformation of 2-chlorobiphenyl to 2-hydroxy-3-chlorobiphenyl by a methanotroph, and is consistent with the formation of an intermediate arene oxide (Adriaens 1994). The occurrence of such intermediates also offers plausible mechanisms for the formation of nitro-containing metabolites that have been observed in the degradation of 4-chlo-robiphenyl in the presence of nitrate (Sylvestre et al. 1982). 

These are the same quinones that are formed when 6-hydroxy-BP is oxidized by air or microsomes (19). However, there is no definitive evidence that 6-hydroxy-BP is an intermediate in their formation by PGH synthase. Among all of the stable metabolites of BP, the quinones are distinctive because, unlike phenols and dihydrodiols, they are not derived from arene oxides. Thus, arene oxides do not appear to be products of BP oxidation by PGH synthase (19,20). 

It is sometimes assumed that every phenol metabolite indicates the formation of an arene oxide intermediate however, as discussed above, arene oxides are not obligate intermediates in the formation of phenols. This is an important distinction because arene oxides and other epoxides are reactive intermediates that can be toxic or even carcinogenic, e.g., epoxides of some polycyclic aromatic hydrocarbons. The question of whether their formation is obligatory is significant for drug design and development and has implications for toxicity as discussed in Chapter 8. 

The observation of a dihydrodiol has been taken as proof that an epoxide (arene oxide) is the precursor metabolite. Many epoxides, such as the 10,11-epoxide of carbamazepine shown above and even the arene oxide of benzene, which is quite reactive, have been directly observed. Others such as the epoxide of phenytoin are only inferred. It is conceivable that some dihydrodiols are formed by reaction of an intermediate with water in the active site of P450 without the formation of an epoxide. One clue to the origin of the dihydrodiol is the stereochemistry an exclusively tram-dihydrodiol suggests that it was formed via the EH-mediated hydrolysis of an epoxide or arene oxide. 

Alkenes may be oxidized to epoxides that are reactive metabolites because of ring strain [36] and can undergo nucleophilic attack. Epoxides are not always highly reactive species. In fact, some of them are relatively unreactive for example, the arene oxides that derive from oxidation of phenyl rings. Most drugs containing a phenyl... 

Conversion of epoxides (arene oxides) into phenols is spontaneous. The conversion of epoxides into dihydrodiols is catalyzed by EH (EC 4.2.1.63). Hydroxyl containing PAHs can act as substrates for conjugases (C) (UDP glucuronsyl transferase (EC 2.4.1.17) and phenol sulphotransferase (EC 2.8.2.1)). This pathway usually leads to inactive excretable products. Epoxides are scavenged by GSH and the reaction is catalyzed by GSHt (EC 2.5.1.18). When GSH is depleted and/or the other pathways are saturated, epoxides of dihydrodiols (particularly 7,8-diol-9,10-epoxides in the case of BP) and phenol metabolites react with cellular macromolecules such as DNA, RNA, and protein. If repair mechanisms are exceeded the detrimental effects of PAH may result. 

In contrast, a number of alkene epoxides (10.3) are chemically quite stable, i.e., intrinsically less reactive than arene oxides. Examples of epoxide metabolites that have proven to be stable enough to be isolated in the absence of degrading enzymes include 1,2-epoxyoctane (10.4), 1,2-epoxycyclohex-ane (10.5), 1-phenyl-1,2-epoxy ethane (styrene oxide, 10.6), and cis- 1,2-diphenyl-1,2-epoxyethane (cfv-stilbene oxide, 10.7) [12], The same is true of alclofenac epoxide (10.8), hexobarbital epoxide (10.9), and a few other epoxides of bioactive compounds. 

As explained in the Introduction, alkene oxides (10.3) are generally chemically quite stable, indicating reduced reactivity compared to arene oxides. Under physiologically relevant conditions, they have little capacity to undergo rearrangement reactions, one exception being the acid-catalyzed 1,2-shift of a proton observed in some olefin epoxides (see Sect. 10.2.1 and Fig. 10.3). Alkene oxides are also resistant to uncatalyzed hydration, thus, in the absence of hydrolases enzymes, many alkene oxides that are formed as metabolites are stable enough to be isolated. 

Bromobiphenyl produced a major metabolite (4% of the dose) identified as either 3-bromo-4-biphenylol or 5-bromo-2-biphenylol a minor dihydroxylated metabolite was also detected. 4-Bromobiphenyl yielded two metabolites 4 -bromo-4-biphenylol (2% of the dose) and 4 -bromo-3,4-biphenyldiol (1.5% of the dose). Experiments witli tritiated 4-bromobiphenyl suggest that the metabolism of this congener involves the formation of an arene oxide. 

PBBs and PBDEs may also cause toxicity by other mechanisms of action. For example, some PBB congeners can be metabolized to reactive arene oxides (Kohli and Safe 1976 Kohli et al. 1978) that may alkylate critical cellular macromolecules and result in injury. PBDEs may disrupt thyroid hormones by induction of hepatic microsomal UDPGT, which increases the rate of T4 conjugation and excretion, or by mimicking T4 or T3 PBDEs and their hydroxy metabolites are structurally similar to these thyroid hormones which are also hydroxy-halogenated diphenyl ethers (see Section 3.5.2). Clinical interventions designed to interfere with this mechanism or the metabolism of PBBs have yet to be developed. 

Recently, the PCB-biodegradative capabilities of methanotrophs have been demonstrated (Adriaens, 1994). In this study, 2-CB was oxidized by a methanotrophic culture (CSC1) to a hydroxylated chlorobiphenyl intermediate identified as 2-hydroxy-3-chlorobiphenyl. This intermediate indicated that the metabolite was formed via a concerted oxidation involving an arene oxide which rearranges spontaneously via an NIH shift. No studies have shown, however, that methanotrophs can degrade more highly chlorinated PCBs, and their utility for bioremediation processes does not seem promising. 

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