Diol Epoxide Pathway

Some drugs fall within the class of functionalized alkenes discussed here. Thus, the anti-inflammatory agent alclophenac (10.63) contains an O-allyl group. Its epoxide was found as a stable metabolite in the urine of mice and humans, and so was the diol, proving the involvement of the epoxide-diol pathway in the metabolism of this drug. The epoxide proved mutagenic, but only in the absence of a rat liver S-9 suspension (which contains EH) [141]. 

A few barbiturates also contain an allylic group at C(5), e.g., allobarbi-tal (10.64, R = allyl), alphenal (10.64, R = Ph), aprobarbital (10.64, R = i-Pr), and secobarbital (10.64, R = 1-methylbutyl). These compounds were substrates of the epoxide-diol pathway in rats and guinea pigs. The relative... 

Fig. 10.17. The epoxide-diol pathway in 5-vinylbarbitu.rates such as vinylbital (10.65, R = 1-methylbutyl). The difference with 5-allylbarbiturates is that the diol metabolite of 5-vinylbar-biturates cannot be isolated due to its immediate decomposition via a retro-aldol-type reaction...

In cattle feces, 64% of the total residues was identified as diethylstilbestrol, 23% as 3-(p-hydroxyphenyl)-2-hexene-4-one, and less than 1% as 4 -hydroxypro-piophenone (43). The identification of 4 -hydroxypropiophenone as a metabolite of diethylstilbestrol implies that dienestrol is formed through an epoxide-diol pathway and that these metabolites show electrophilic reactivity (45). These observations have to be seen in connection with the mutagenic and carcinogenic activity of diethylstilbestrol and possibly also the other stilbene estrogens. 

C Pantarotto, L Cappellini, A De Pascale, A Frigerio. Epoxide-diol pathway in the metabolism of 5H-dibenzo[b,f -azepine (iminostilbene). 1 Chromatogr 134 307-314, 1977. 

It has also been suggested that valproate is not a selective inhibitor of epoxide hydrolase but that it inhibits all the steps of the epoxide-diol pathway. The trans-diol metabolite is then further converted by glueuronida-tion, and it seems that this step is also inhibited. ... 

Stillwell WG, Stafford M, Horning MG (1973) Metabolism of glutethimide (doriden) by the epoxide-diol pathway in the rat and guinea pig. Res Commun Chem Pathol Pharmacol 6 579-590... 

Isoeugenol is converted to vanillin through an epoxide-diol pathway leading to vanillyl alcohol as a precursor. The intermediates isoeugenol oxide and isoeugenol diol were identified in the biotransformation of isoeugenol with Bacillus pumilus S-1, which afforded 3.75 gl yield of vanillin in preparative biotransformation [39]. 

RELATIONSHIP BETWEEN STRUCTURE AND METABOLISM OF TRICYCLIC DRUGS STABLE EPOXIDE-DIOL PATHWAY... 

The glutathione 5-transferase pathway is sometimes in biochemical competition with the epoxide hydratase pathway, in that both deactivate intermediates of the MMFO. Epoxide hydratase is a microsomal enzyme that acts specifically to deactivate epoxide intermediates, by the addition of water across the C—O bond to form a diol. As a very broad generality, the glutathione 5-transferase pathway tends to be more prominent in rodents, while the epoxide hydratase pathway tends to be more dominant in nonrodents. 

In contrast, the pathway best known to yield adduct-forming metabolites (the ultimate carcinogens) is the formation of dihydrodiol epoxides, usually referred to as diol epoxides . This pathway involves three steps a) formation of an M-region epoxide, b) its hydration to the M-region dihydrodiol, and c) epoxidation of the latter at the vicinal C=C bond bordering the bay or fjord region. 

Omzigt JGC, Los FJ, Meijer JWA, et al. The 10,ll-epoxide-10,ll-diol pathway of carbamazepine in early pregnancy in maternal serum, urine, and amniotic fluid effect of dose, comedication, and relation to outcome of pregnancy. Ther Drug Monit 1993 15 1-10. 

Danazol inhibits the metabolism (by the epoxide-trans-diol pathway) of carbamazepine by the liver, thereby reducing its loss from the body. During danazol treatment the clearance of carbamazepine has been found to be reduced by 60%. ... 

Biotransformation studies of these compounds were carried out both in vitro , by incubation with rat liver microsomes, and in vivo , in rat and, for clinically used drugs, also in man. The original hypothesis of the involvement of an "epoxide-diol metabolic pathway common to all the listed drugs has been confirmed be means of chromatographic and mass spectrometric techniques (17, 22). 

Some such pathway is necessary to account for the migration of oxygen that is found. It may involve a protonated epoxide, a 1,2-diol, or simply a 1,2 shift of an OH group. 

The key to the success of the vinyl epoxide route would reside in a nucleophilic ring-opening of vinyl epoxide 75. If this ring-opening proceeds regioselectively at C5 via a SN2 pathway, it would have been the most welcome at this stage of our efforts (Scheme 8.21). However, an array of conditions, including Pd(0)-mediated and Lewis acidic conditions, were screened over a period of almost 2 years, but we never observed the desired 1,4-diol 80. Instead, we could at various times see small... 

A potentially powerful probe for sorting out the contribution of hydroperoxide-dependent and mixed-function oxidase-dependent polycyclic hydrocarbon oxidation is stereochemistry. Figure 9 summarizes the stereochemical differences in epoxidation of ( )-BP-7,8-dihydrodiol by hydroperoxide-dependent and mixed-function oxidase-dependent pathways (31,55,56). The (-)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (+)-anti-diol epoxide by both pathways whereas the (+)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (-)-anti-diol epoxide by hydroperoxide-dependent oxidation and to the (+)-syn-diol epoxide by mixed-function oxidases. The stereochemical course of oxidation by cytochrome P-450 isoenzymes was first elucidated for the methycholanthrene-inducible form but we have detected the same stereochemical profile using rat liver microsomes from control, phenobarbital-, or methyl-cholanthrene-induced animals (32). The only difference between the microsomal preparations is the rate of oxidation. 

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