Hydrolytic pathway, metabolism

The metabolism of fluorobenzoates has been examined over many years. Early studies using Nocardia erythropoUs (Cain et al. 1968) and Pseudomonas fluorescens (Hughes 1965) showed that although the rates of whole-cell oxidation of fluorobenzoates were less than for benzoate, they were comparable to, and greater than for, the chlorinated analogs. As for their chlorinated analogs, both dioxygenation and hydrolytic pathways may be involved, and studies have revealed that the different pathways depended on the positions of the fluorine substituents. 

Figure 9.3. The two main pathways for metabolism of PTX-2 in shellfish. The oxidative pathway has so far been confirmed only in P. yessoensis. The hydrolytic pathway appears to occur in all other shellfish species studied, including mussels, clams, and other species of scallop.

PCB arene oxides can also generate dihydrodiols via a hydrolytic pathway mediated by microsomal epoxide hydrolase, although metabolism to monohydroxy-metabolites is more commonly observed [74,75]. OH-PCBs are susceptible to further metabolism, i. e. conjugation reaction with glucuronic acid or sulfate, which increases the water solubility and facilitates excretion. Glucuronic acid and sulfate conjugates of several PCB congeners have been determined in bile and urine from experimental animals exposed to the PCBs [50,76,77]. Biliary excretion is the preferred pathway for PCB metabolites, whereas only a small portion is excreted via the urine [77]. 

Drugs are metabolized via oxidative, reductive, and hydrolytic pathways (phase... 

Figure 1. Hydrolytic pathway of metabolism of the insecticide carbaryl Once considered the only route of metabolism, radio-tracer studies later showed that oxidation, hydrolysis and conjugation reactions resulted in over a dozen metabolites being formed by some organisms.

Phosphonate analogs to phosphate esters, in which the P—0 bond is formally replaced by a P—C bond, have attracted attention due to their stability toward the hydrolytic action of phosphatases, which renders them potential inhibitors or regulators of metabolic processes. Two alternative pathways, in fact, may achieve introduction of the phosphonate moiety by enzyme catalysis. The first employs the bioisosteric methylene phosphonate analog (39), which yields products related to sugar 1-phosphates such as (71)/(72) (Figure 10.28) [102,107]. This strategy is rather effective because of the inherent stability of (39) as a replacement for (25), but depends on the individual tolerance of the aldolase for structural modification close... 

NADPH-independent hydrolytic metabolism. The CLint for deltamethrin was estimated to be twice as rapid in humans as in rats on a per kg body weight basis. Metabolism by purified rat and human CESs was used to examine further the species differences in hydrolysis of deltamethrin and esfenvalerate. Results of CES metabolism revealed that hCEl was markedly more active toward deltamethrin than the Class I rat CESs, hydrolase A and B, and the Class II human CES, hCE2 however, hydrolase A metabolized esfenvalerate twice as fast as hCEl, whereas hydrolase B and hCEl hydrolyzed esfenvalerate at equal rates. These studies demonstrated a significant species difference in the in vitro pathways of biotransformation of deltamethrin in rat and human liver microsomes, which was due in part to differences in the intrinsic activities of rat and human CESs. 

Fig. 4.2 Hydrolytic activity of cauxin on 3-MBCG and proposed metabolic pathways for the conversion of 3-MBG to felinine in the cat kidney. The 3-MBCG (20 mM) was incubated with or without cauxin (1.5 mg/ml) at 38°C for 6 h, and the reaction mixtures were analyzed by thin layer chromatography with ninhydrin staining. y-GTP, y-glutamyl transferase RDP, renal dipeptidase a, 3-mercapto-3-methylbutyl formate b, 3-mercapto-3-methyl-l-butanol c, 3-methyl-3-methylthio-1-butanol and d, 3-methyl-3-(2-methyldisulfanyl)-l-butanol...

The metabolism of C-DEHP by rainbow trout liver subcell-ular fractions and serum was studied by Melancon and Lech (14). The data in Table VI show that without added NADPH, the major metabolite produced was mono-2-ethylhexyl phthalate. When NADPH was added to liver homogenates or the mitochondrial or microsomal fractions, two unidentified metabolites more polar than the monoester were produced. Additional studies showed that the metabolism of DEHP by the mitochondrial and the microsomal fractions were very similar (Figure 1). Both fractions show an increased production of metabolites of DEHP resulting from addition of NADPH and the shift from production of monoester to that of more polar metabolites. The reduced accumulation of monoester which accompanied this NADPH mediated production of more polar metabolites may help in interpreting the pathway of DEHP metabolism in trout liver. This decreased accumulation of monoester could be explained either by metabolism of the monoester to more polar metabolites or the shift of DEHP from the hydrolytic route to a different, oxidative pathway. The latter explanation is unlikely because in these experiments less than 20% of the DEHP was metabolized. 

Antibacterial sulfonamides contain two N-atoms, the sulfonamido (N1) and the para primary amino (N4). The sulfonamido group, in contrast to a carboxamido group, is chemically and metabolically stable. In other words, hydrolytic cleavage of sulfonamides to produce a sulfonic acid and an amine has never been observed. We, therefore, focus our discussion on the primary amino group, acetylation of which is one of the major metabolic pathways for some sulfonamides. Hydrolysis of the N4-acety luted metabolites back to the parent sulfonamide can occur in the liver, kidney, and intestinal tract. The reaction is strongly influenced by the structure of the parent amine e.g., N4-acetylsulfisoxazole (4.121) was deacetylated by intestinal bacteria whereas /V4-acctyIsulI anilamide (4.122) under identical conditions was not [78][79],... 

The herbicide alachlor (4.146, Fig. 4.7) also displayed species-dependent toxicity, since it induced nasal tumors in rats but not in mice. Its metabolic scheme in rats and mice (Fig. 4.7) shows that alachlor can be transformed into 2,6-diethylaniline (4.149) by two different pathways, one of which proceeds via formation of 4.147. The other pathway implies glutathione (GSH) conjugation, followed by /3-lyase-mediated liberation of the thiol, followed by S-methylation to produce the methylsulfide 4.148. The two secondary amides 4.147 and 4.148 were hydrolyzed by microsomal arylamidases, but alachlor itself was not a substrate for this enzyme. The hydrolytic product 2,6-diethylaniline (4.149) was oxidized in nasal tissues to the electrophilic quinonimine metabolite 4.150, which can bind covalently to proteins. Aryl-... 

After oral administration of ameltolide (4.143, Fig. 4.6) to rats, no hydrolytic products were detected in biological fluids [103], One could argue that the two o-Me groups afforded steric protection to the amide bond. However, steric hindrance may not be the main reason for the absence of metabolic cleavage in this compound, since, for lidocaine (4.12, Fig. 4.5), cleavage of the amide bond represents a major metabolic route in mammals. The apparent absence of hydrolysis in the metabolism of ameltolide may be caused by the predominance of major alternative pathways, namely A-acetylation and hydroxylation. Furthermore, the small fraction of unidentified polar metabolites may contain some products of hydrolysis. 

Marked species differences in hydrolytic cleavage were also observed for pranlukast (4.160), a leukotriene receptor antagonist. In rats, amide hydrolysis represented a major metabolic pathway, whereas, in humans, it was apparently absent. Investigations with purified enzymes showed that pranlukast... 

A. A. Elfarra, R. J. Krause, R. R. Selzer, Biochemistry of 1,3-Butadiene Metabolism and Its Relevance to 1,3-Butadiene-Induced Carcinogenicity , Toxicology 1996, 113, 23 - 30 R. A. Kemper, R. J. Krause, A. A. Elfarra, Metabolism of Butadiene Monoxide by Freshly Isolated Hepatocytes from Mice and Rats Different Partitioning between Oxidative, Hydrolytic, and Conjugations Pathways , Drug Metab. Dispos. 2001, 29, 830 - 836. 

The most important example to be discussed here is that of the drug chloramphenicol (11.39, R = 2-hydroxy-l-(hydroxymethyl)-2-(4-nitrophen-yl)ethyl, Fig. 11.7), the many metabolic pathways of which have yielded a wealth of information [75], The dichloroacetyl moiety is especially of interest in that dechlorination proceeds by three proven routes glutathione-dependent dechlorination, cytochrome P450 catalyzed oxidation, and hydrolysis. Of particular value is that the oxidative and hydrolytic routes can be unambiguously distinguished by at least one product, as shown in Fig. 11.7. Oxidation at the geminal H-atom produces an unstable (dichloro)hydroxyacet-amido intermediate that spontaneously eliminates HC1 to yield the oxamoyl... 

In conclusion, the oxamic acid derivative is produced by two distinct metabolic pathways, namely by oxidative and hydrolytic dechlorinations. In contrast, the primary alcohol metabolite 11.41 can be produced only by hydrolytic dechlorination and is, thus, an unambiguous marker of this pathway. The alcohol 11.41 is a known urinary metabolite of chloramphenicol in humans. 

Polyhydroamino acids, thermal, reactions catalyzed by,20 379 aminations, 20 405-408 decarboxylations, 20 394-405 hydrolytic, 20 380-394 metabolic pathways, 20 408 Polyion reagents, seespecific substances Polymer chains, growth of, on Ziegler catalysts, 19 225-228... 

Disposition Metabolic studies indicate hydrolytic release of the calicheamicin derivative from gemtuzumab ozogamicin. Many metabolites of this derivative were found after in vitro incubation of gemtuzumab ozogamicin in human liver microsomes and cytosol, and in HL-60 promyelocytic leukemia cells. Metabolic studies characterizing the possible isozymes involved in the metabolic pathway of Mylotarg have not been performed. 

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