NADPH-dependent oxidative metabolism

The species differences in biotransformation pathways, rates of elimination, and intrinsic hepatic clearance of esfenvalerate and deltamethrin using rat and human liver microsomes were examined [33]. Esfenvalerate was eliminated primarily via NADPH-dependent oxidative metabolism in both rat and human liver microsomes. The CLint of esfenvalerate was estimated to be threefold greater in rodents than in humans on a per kg body weight basis. Deltamethrin was also eliminated primarily via NADPH-dependent oxidative metabolism in rat liver microsomes however, in human liver microsomes, deltamethrin was eliminated almost entirely via... 

The metabolic pathways leading to the production of these urinary pyridinium metabolites are likely to be mediated by one or more forms of liver cytochrome P450. In vitro metabolic studies with rodent (Igarashi et al., unpublished results) and human (Usuki et al., submitted) microsomal preparations have demonstrated the NADPH-dependent oxidation of both HP and HPTP to HPP. Ongoing studies in the authors laboratory have shown that HPP and related pyridinium metabolites are present in brain tissues obtained from C57 black mice that had been treated with HPTP (Van der Schyf et al. 1994). Additionally, results obtained from intra-cerebral microdialysis, mitochondrial respiration, and rat embryonic mesencephalic cell culture studies suggest that HPP possesses MPP type neurotoxic properties (Rollema et al. 1992, 1994 Bloomquist et al. 1994). 

Detoxification of organophosphorus pesticides before they can reach their target sites is probably the main reason for poor correlation between carcinogenicity and electrophilicity/mutagenicity. The problem is further complicated by the fact that several different enzymes are involved in the metabolic detoxification of organophosphorus pesticides. For example, paraoxon, tetrachlojTvinphos and dimethoate are preferentially detoxified by A-esterase (paraoxonase), GSH-dependent S-alkyltransferase and carboxyesterase (aliesterase), respectively whereas chlorfenvinphos is mainly detoxified by NADPH-dependent oxidative dealkylation... 

Tsemg, K.-Y. Jin, SJ. (1991) J. Biol Chem., 266, 11614-11620, NADPH-dependent reductive metabolism of cis-5 unsaturated fatty acids. A revised pathway for the beta-oxidation of oleic acid. 

Coenzyme M was shown to function as the central cofactor of aliphatic epoxide carboxylation in Xanthobacter strain Py2, an aerobe from the Bacteria domain (AUen et al. 1999). The organism metabolizes short-chain aliphatic alkenes via oxidation to epoxyalkanes, followed by carboxylation to p-ketoacids. An enzyme in the pathway catalyzes the addition of coenzyme M to epoxypropane to form 2-(2-hydroxypropylthio)ethanesulfonate. This intermediate is oxidized to 2-(2-ketopropylthio)ethanesulfonate, followed by a NADPH-dependent cleavage and carboxylation of the P-ketothioether to form acetoacetate and coenzyme M. This is the only known function for coenzyme M outside the methanoarchaea. 

Concerning the metabolism of triterpenes and steroids, quite a number of P450 catalyzed transformations are very important, namely the 14a-demethyla-tion of lanosterol [50], the side-chain cleavage of cholesterol [51]and pregnenes [52], and the desaturation of ring A of androgens with concomitant oxidative removal of C(19) [53]. The latter reaction is catalyzed by human placental aromatase, associated with a NADPH-dependent reductase, and requires three moles of oxygen and three moles of NADPH in order to oxidize andro-stenedione 45 to formic acid and estrone 46, Fig. 10. 

When the taurine chloramine uptake rate exceeds the rate of NADPH-dependent regeneration of GSH, there is a net loss of cellular GSH level, causing protein-thiol oxidation, ATP loss, and disruption of cellular metabolism. Heme moieties are the other target of chloramine attack on cellular constituents. Oxidation of hemoglobin to methemoglobin (and other hemoproteins to their oxidized derivatives) occurs at 10-fold excess of chloramine taurine molar concentration compared... 

In vitro metabolic studies with rodent and human liver microsomal prepara- tions have established that MPTP undergoes both oxidative N-demethylation and C-6 (allylic) oxidation in reactions that are -nicotinamide adenine dinucleotide phosphate (NADPH) dependent and therefore likely to be cytochrome P-450 catalyzed (Weissman et al. 1985 Ottoboni et al. 1990). Although the latter transformation can lead to the toxic pyridinium metabolite MPP, the cytochrome P450-catalyzed pathway is unlikely to contribute significantly to the neurotoxicity of MPTP. As mentioned above, liver aldehyde oxidase diverts the inter-mediate dihydropyridinium metabolite away from pyridinium ion formation by catalyzing the conversion of structure 40 to the nontoxic lactim structure 41. Further-more, even if formed in the periphery, the polar pyridinium metabolite would have limited access to the central nervous system (CNS). The low... 

Hlavica, P. and U. Kiinzel-Mulas (1993). Metabolic N-oxide formation by rabbit-liver microsomal cytochrome P-4502B4 Involvement of superoxide in the NADPH-dependent N-oxygenation of N,N-dimethylaniline. Biochim. Biophys. Acta 1158, 83-90. 

Reductive biotransformations of several compounds such as polyhalogenated, keto, nitro and azo derivatives, are catalysed by a variety of enzymes which differ according to the substrates and the species. The liver cytochrome P-450-dependent drug metabolizing system is capable of reducing Af-oxide, nitro and azo bonds, whereas the cytosolic nitrobenzene reductase activity is mainly due to cytochrome P-450 reductase, which transforms nitrobenzene into its hydroxylamino derivative. NADPH cytochrome c reductase is also able to catalyse the reduction of nitro compounds. These metabolic conversions may also be brought about by gastrointestinal anaerobic bacteria. 

Studies by Hodgson and Casida (1960, 1961) were the first investigations of CM oxidation by microsomal NADPH-dependent enzymes. There is evidence that oxidation is the more important route for some CM metabolism, not only in a pharmacokinetic but also in a toxicological perspective because, unlike hydrolysis that usually generates detoxication products, oxidative metabolites often retain the CM ester bond and can sometimes have more potent anti-ChE activity (Oonnithan and Ca.sida, 1968). 

Why more appealing For one thing, oxidative changes are much more common in the body than reductive changes. For another, the conversion of amphetamine to N-hydroxyamphetamine is an intermediate in the conversion of amphetamine to phenylacetone, a known metabolic process in several animal species. And that intermediate, N-hydroxyamphetamine, is a material that gives the famous cytochrome P-450 complex that has fascinated biochemists studying the so-called NADPH-dependent metabolism. 

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