Metabolite postulated mechanisms

Fig. 9.11. Postulated mechanism of cytochrome P450 catalyzed phosphoric acid ester cleavage of the bisphophonate U-91502 (9.51) to produce a triester metabolite 9.52 [118]...

Rats exposed to a fteptone-containing atmosphere excreted a variety of metabolites resulting from oxidative pathways [176]. The major metabolites were isomeric mono-alcohols and ketones, but small amounts of 2-ethyl-5-methyl-2,3-dihydrofuran (11.171, R = Et, R = Me, Fig. 11.22,a) and 5-ethyl-2-methyl-2,3-dihydrofuran (11.171, R = Me, R = Et) were also detected. These metabolites are believed to arise from 6-hydroxyheptan-3-one (11.170, R = Et, R = Me) and 5-hydroxyheptan-2-one (11.170, R = Me, R = Et). The postulated mechanism of formation of 2,3-dihydrofurans involves their equilibrium with the corresponding linear y-hydroxy ketones, as shown in Fig. 11.22,a. Such a reaction has been documented for linear y-hydroxy aldehydes [177],... 

Figure 1. Postulated mechanisms of toxicity by chemically reactive metabolites...

Physiology is the study of function. The classical procedure used to define physiological roles is by extirpation, ablation or nerve section to reveal inadequate or inappropriate function in the absence of the postulated mechanism. This approach cannot be used to study the physiological role of arachidonate metabolites since they are not organ-localized like the adrenal steroids or concentrated in specific cells like the adrenergic transmitters. The problem is compounded also by the fact that arachidonate oxygenation is almost a universal phenomenon. Finally the metabolites are not stored like histamine or serotonin but are released immediately upon synthesis. Consequently it is always necessary to initiate synthesis to study release. Thus release is synonymous with synthesis. 

The cause of this complication is not known. One postulated mechanism is direct damage to the urinary tract mucosa from metabolites of ketamine causing submucosal inflammation and eventually edema and fibrosis microvascular changes may compromise the intrinsic microcirculation, causing neovascularization. The preponderance of abnormalities in the lower urinary tract may be due to increased time spent in contact with ketamine metabolites. 

Postulated mechanism for hydrazine toxicity. Previous work (11) has provided evidence that acetylhydrazine is the metabolite of ioniazid and that isopropylhydrazine is the metabolite of... 

Bromoethylamine (11.133, R = Br, Fig. 11.18) is a potent nephrotoxin used to create an experimental model of nephropathy. Its mechanism of toxicity is postulated to involve perturbation of mitochondrial function, and its metabolism was investigated in a search for toxic metabolites. In rat plasma, 2-bromoethylamine was converted to aziridine (11.134), formed by intramolecular nucleophilic substitution and bromide elimination [155], Another major metabolite was oxazolidin-2-one (11.136). This peculiar metabolite resulted from the reaction of 2-bromoethylamine with endogenous carbonate to form carbamic acid 11.135, followed by cyclization-elimination to oxazoli-din-2-one. In aqueous media containing excess carbonate, the formation of... 

Fig. 11.22. Mechanisms postulated for cyclodehydration of a) linear y-hydroxy ketones (11.170) as metabolites of alkanes and alkanones to form 2,5-dialkyl-2,3-dihydrofurans (11.171), and b) piroxicam (11.172) to form its cyclodehydrated metabolite 11.173...

Shimabukuro et al. (1966) identified 2-chloro-4-amino-6-isopropylamino-i-triazine (G-30033) as a major metabolite in shoots of mature pea plants. These results indicated that a second mechanism for tolerance to atrazine existed in some moderately susceptible plants. Later, Shimabukuro (1967a) was able to demonstrate that atrazine could be metabolized independently in both roots and shoots of young pea plants to 2-chloro-4-amino-6-isopropylamino-.t-triazine. This metabolite was much less phytotoxic than the parent compound. The metabolism of atrazine in resistant com and sorghum, in intermediately susceptible pea, and in highly susceptible wheat was reported by Shimabukuro (1967b). This study revealed two possible pathways for metabolism of atrazine in higher plants. All species studied were able to metabolize atrazine by TV-deal kyI ation of either of the two alkyl groups present. Com and wheat that contain the cyclic hydroxyamate (2,4-dihydroxy-7-methoxy-l,4-benzoxazine-3-one) also metabolized atrazine by conversion to hydroxy-atrazine (G-34048). Subsequent metabolism was postulated to be by conversion to more polar compounds. 

The mechanism by which PfCRT confers resistance to chloroquine is still under discussion [75], The first aspect concerns the nature of the protein whether PfCRT, postulated to possess ten transmembrane helices, is considered as a member of the drug-metabolite transporter family of proteins [55, 76-78], Some authors discuss about the channel nature of the protein [79, 80], It has been suggested that the change of the charged lysine to uncharged threonine affects the electrostatic interaction with the diprotonated CQ [81]. In the mutated forms, the absence of electrostatic interactions allows the drug to cross the channel (Fig. 6). This results in the efflux of the drug out of the DV [81]. Note here that the reduced accumulation can be partially reversed by verapamil, a lipophilic compound (Fig. 5). 

The widespread use of isoniazid prophylaxis for tuberculosis has focused attention on the liver injury caused by this drug. About 20% of patients treated with isoniazid will show elevated blood concentrations of liver enzymes and bilirubin that subside as treatment is continued (25). However/ clinical hepatitis develops in some patientS/ and these reactions can prove fatal. Current understanding of the mechanism of isoniazid-induced hepatotoxicity is based on the metabolic pathways shown in Figure 16.6 (26/ 27). It has been demonstrated in an animal model that hepatotoxicity is correlated with plasma concentrations of hydrazine but not of acetylhydrazine or isoniazid (28)/ and that pretreatment with an amidase inhibitor can prevent toxicity (27). However/ it is postulated that hydrazine is further metabolized to a chemically reactive he pa to toxin by the cytochrome P450 system/ and in vitro studies with hepatocytes have implicated CYP2E1 as the cytochrome P450 isoform responsible for cytotoxic metabolite formation (29). 

Based on the structural diversity of the many congeners originating from Laurencia, the elucidation of a bios5mthetic mechanism for the likely development of these metabolites is of much interest. The isolation and characterization of monoepoxide 30 (Scheme 1) from Laurencia okamurai [15] has allowed investigators to postulate that this compound (30) may be a common precursor for the biosynthesis of all other secondary metabolites derived from squalene [3]. Its absolute stereochemistry was verified via asymmetric synthesis utilizing a Sharpless asymmetric epoxidation [16] of trans, trara-famesol,... 

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