Acetylation, biotransformation

Sulfisoxazole is metabolized to its N -acetyl derivative which is the major metabolite found in human urine. Sulfisoxazole is ultimately eliminated from the body solely by means of urinary excretion with a mean of 54 percent of the dose excreted as the "free" drug and the remainder as the N4-acetylated biotransformation product (15). 

Biotransformation reactions can be classified as phase 1 and phase 11. In phase 1 reactions, dmgs are converted to product by processes of functionalization, including oxidation, reduction, dealkylation, and hydrolysis. Phase 11 or synthetic reactions involve coupling the dmg or its polar metaboHte to endogenous substrates and include methylation, acetylation, and glucuronidation (Table 1). 

In principle, numerous reports have detailed the possibility to modify an enzyme to carry out a different type of reaction than that of its attributed function, and the possibility to modify the cofactor of the enzyme has been well explored [8,10]. Recently, the possibility to directly observe reactions, normally not catalyzed by an enzyme when choosing a modified substrate, has been reported under the concept of catalytic promiscuity [9], a phenomenon that is believed to be involved in the appearance of new enzyme functions during the course of evolution [23]. A recent example of catalytic promiscuity of possible interest for novel biotransformations concerns the discovery that mutation of the nucleophilic serine residue in the active site of Candida antarctica lipase B produces a mutant (SerlOSAla) capable of efficiently catalyzing the Michael addition of acetyl acetone to methyl vinyl ketone [24]. The oxyanion hole is believed to be complex and activate the carbonyl group of the electrophile, while the histidine nucleophile takes care of generating the acetyl acetonate anion by deprotonation of the carbon (Figure 3.5). 

Since there is no commercially available D-aminoacylase, the production process of D-amino acids involves cloning of the D-aminoacylase and the whole cells containing the recombinant d-aminoacylase are used in biotransformation of /V-acetyl-D-amino acid, d-Amino acids can be generated in large quantities at low cost using whole-cell biotransformation [23]. 

Acetylated MS-222 was found in much higher concentrations in the urine than in the blood of rainbow trout. This suggests that the kidney concentrated the drug metabolite, or that MS-222 was acetylated in the kidney and excreted in the urine (28). Weber (31) stated that acetylation of p-aminobenzoic acid and sulfamethazine is catalyzed by most of the tissues in the body. He showed that in rabbits the acetylation of these amines by the kidney of rabbit is a small percentage of the total acetylation capability, but that the kidney is involved in this biotransformation. 

The metabolism of taxol by Eucalyptus perriniana cell suspension cultures has been recently reported to induce hydrolyses of ester bonds at C-13, C-10 and C-2 [222]. At this moment only very few data have been published about the microbial metabolism of taxoid compounds only site specific hydrolyses of acyl side-chains at C-13 or C-10 by extracellular and intracellular esterases of Nocar-dioides albus SC13,911 and N. luteus SC13,912, respectively, have been reported [223]. On the other hand, Hu et al. [224-226] have recently described some fungal biotransformations of related natural taxane diterpenes extracted from Chinese yews or their cell cultures, in order to obtain new active substances or precursors for hemisynthesis. The taxadiene 145, a 14 -acetylated derivative... 

As an example, acetaminophen (APAP) in overdose has been used by several groups to identify hepatotoxicity biomarkers in mice. APAP-induced hepatotoxicity is characterized by hepatic centrilobular necrosis and hepatitis. APAP biotransformation by Phase I enzymes leads to the formation of the reactive metabolite N-acetyl-p-benzoquinone (NAPQI), which can deplete glutathione and form adducts with hepatic proteins (see Section 15.2). Protein adduction primes the hepatocytes for cytokines released by activated macrophages (Kupffer cells) and/or destructive insults by reactive nitrogen species. Although necrosis is recognized as the mode of cell death in APAP overdose, the precise mechanisms are still being elucidated [152]. 

Metabolism of isoniazid, especially acetylation by liver/V-acetyltransferase, is genetically determined (see Chapter 4 Drug Biotransformation). The average concentration of isoniazid in the plasma of rapid acetylators is about one third to one half of that in slow acetylators and average half-lives are less than 1 hour and 3 hours, respectively. Rapid acetylators were once thought to be more prone to hepatotoxicity, but this has not been proved. More rapid clearance of isoniazid by rapid acetylators is of no therapeutic consequence when appropriate doses are administered daily, but subtherapeutic concentrations may occur if drug is administered as a once-weekly dose. 

Phase 1 reactions Oxidative reactions involving N- and O-dealkylation, aliphatic and aromatic hydroxylation, N- and S-oxidation, deamination. Phase 2 reactions Biotransformation reactions involving glucuronization, sulphation, acetylation. 

Figure 1 Structural and bioconverting relationships among tylosin, AIV, and its related acyltylosins. (A) Chemical structures of tylosin, AIV, and its related acyltylosins. (B) Biotransformation of tylosin to AIV by two types of macrolide acyltransferases in S. ther-motolerans 3-O-acyltransferase and 4"-0-acyltransferase catalyze acetylation at the 3-hydroxyl group of tylonolide and isovalerylation at the 4"-hydroxyl group of mycarose, respectively.

Alachlor is also known to be biotransformed under anaerobic conditions, with acetyl alachlor the transformation product of hydrogenolysis [46]. Transformation kinetics were modeled as a second-order reaction ... 

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