Metabolism oximes

NAUR, P., PETERSEN, B.L., MIKKELSEN, M.D., BAK, S RASMUSSEN, H., OLSEN, C.E., HALKIER, B.A., CYP83A1 and CYP83B1, two nonredundant cytochrome P450 enzymes metabolizing oximes in the biosynthesis of glucosinolates in Arabidopsis., Plant Physiol., 2003, 133, 63-72. 

The first drugs in this class to be introduced into clinical practice are simple derivatives of 5-nitrofurfural (18). Thus, the oxime is known as nitrofuroxime (19) while the semicarbazone is called nitrofurazone (20). In order to maintain better control over the distribution and metabolism of these antibacterial agents, increasingly complex side chains and rings have been grafted onto the hydrazone. 

With aldicarb, primary metabolic attack is again by oxidation and hydrolysis. Hydrolytic cleavage yields an oxime and represents a detoxication. Oxidation to aldicarb sulfoxide and sulfone, however, yields products that are active anticholinesterases. Carbofuran is detoxified by both hydrolytic and oxidative attack. 

HydroxyNPYR [ ] has been identified as a urinary metabolite of NPYR in the rat (up to 1% of the dose), but was not detected when NPYR was incubated with subcellular fractions from rat liver and lung (13, 20). It has been proposed that further metabolism of leads to dimethy 1 amine, [ ], another urinary metabolite of NPYR, 2-Pyrrolidinone [3 ] has also been detected in the urine of rats treated with NPYR. Its origin has not been conclusively established, but it may form from pyrrol id inone-2-oxime (i6). 

CYP79s in the Biosynthesis of Cyanogenic Glucosides and Glucosinolates 233 The Oxime-Metabolizing Enzyme as Branch Point between the Cyanogenic... 

Molecular Identification of Oxime-Metabolizing Enzyme in Glucosinolate... 

THE OXIME-METABOLIZING ENZYME AS BRANCH POINT BETWEEN THE CYANOGENIC GLUCOSIDE AND THE GLUCOSINOLATE PATHWAY... 

S. alba has been used as a model plant for biochemical studies of the oxime-metabolizing enzyme in the biosynthetic pathway of glucosinolates.33 The major... 

Figure 13.5 Metabolic engineering of oxime-derived natural products in Arabidopsis plants. Up- and downregulation of endogenous as well as exogenous CYP79s provides a powerful tool for alteration of the glucosinolate profiles and introduction of novel glucosinolates, as well as for engineering oxime-derived natural products.

Like imines, some oximes are known to undergo metabolic hydrolysis by a nonenzymatic mechanism. Cyclohexanone oxime (11.69), an intermediate in the synthesis of polycaprolactam or Nylon-6, is a good example with which to begin our discussion. Following administration to male rats by various routes, cyclohexanone oxime undergoes rapid metabolism, and only trace amounts of the parent compound can be recovered in the urine [104], Although cyclohexanone (11.70) represented a small fraction of the urinary metabolites, most of the dose was recovered as glucuronides of cyclohexa-nol (11.71) and of cis- and /ran.v-cyclohexanc-1,2-diol. 

In vitro studies on rat liver preparations confirmed the postulated metabolic pathway of nonenzymatic hydrolysis of the oxime 11.69 to the ketone 11.70, followed by enzymatic reduction to 11.71, hydroxylation to diols, and glucuronidation. Clearly, the first step in this metabolic scheme is the nearly quantitative hydrolysis of the oxime to the ketone. 

A complicating factor in the metabolism of oximes arises from the possibility that they become reduced to the imine (RR C=NH) prior to hydrolysis, thus releasing NH3 rather than hydroxylamine (H2N-OH) as the primary metabolite. Evidence for this indirect pathway of hydrolysis comes from a study of the effect of a variety of selective enzyme inhibitors on the metabolism of butanal oxime (11.72) in rats [105]. 

D. Parmar, L. T. Burka, Metabolism and Disposition of Cyclohexanone Oxime in Male F-344 Rats , Drug Metab. Dispos. 1991, 19, 1101 - 1107. 

Andrawes, N.R., Bagley, W.P., and Herrett, R.A. Fate and carryover properties of Temik aldicarb pesticide [2-methyl-2-(methylthio)propionaldehyde 0-(methylcarbamoyl)oxime] in soil, J. Agric. Food Chem., 19(4) 727-730, 1971. Andrawes, N.R., Romine, R.R., and Bagley, W.P. Metabolism and residues of Temik aldicarb pesticide in cotton foliage and under field conditions, J. Agric. Food Chem., 21(3) 379-386, 1973. 

Bull, D.L. Metabolism of UC-21149 [2-methyl-2-(methylthio)propionaldehyde 0-(methylcarbamoyl)oxime] in cotton plants and soil in the field, J. Econ. Entomol, 61 1598-1602, 1968. 

Metcalf, R.L., Fukuto, T.R., Collins, C., Borck, K., Burk, J., Reynolds, H.T., and Osman, M.F. Metabolism of 2-methyl-(2-methylthio)propionaldehyde 0-(methylcarbamoyl)oxime in plant and insect, 7 Agric. Food Chem., 14(6) 579-584, 1966. 

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