Acetylation, deacetylation and acyltransfer

King, Charles M.; Glowinski, Irene B.

doi:10.1289/ehp.834943

Cited by 74 publications

(24 citation statements)

References 23 publications

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“…Although the hydrolysis pathway was observed during in vitro experiments using dog liver S9 fractions, the nonreversible deacetylation of the B-ring acetamido group (Gao et al, 2006a) makes the metabolite more difficult to separate and detect in in vivo biological samples. The lack of N-acetyltransferase activity in dogs (King and Glowinski, 1983) was also responsible for our observation that the deacetylated metabolite M5 was observed in the dog, but not in the rat.…”

Section: Discussionmentioning

confidence: 77%

In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

Perera¹,

Yin²,

Wu³

et al. 2006

Drug Metabolism and Disposition

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ABSTRACT:Compound S-4 (S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide) is a novel nonsteroidal androgen agonist that mimics many of the beneficial pharmacologic effects of testosterone with lesser effects on the prostate. S-4 demonstrated high androgen receptor binding affinity as well as anabolic specificity during in vivo pharmacologic studies in rats, identifying it as the first member of a new class of selective androgen receptor modulators. The purpose of these studies was to determine the pharmacokinetics and metabolism of S-4 in dogs. S-4 showed linear pharmacokinetics after both intravenous (i.v.) and oral (p.o.) administrations at pharmacologically relevant doses, with a mean clearance of 4.6 ml/min/kg and a mean half-life of about 200 min. It is interesting that dose-dependent oral bioavailability was seen. However, at pharmacologically relevant doses, the oral bioavailability of S-4 was 91%. Species differences were observed in S-4 metabolism; the major metabolic pathway for S-4 in dogs was deacetylation of the B-ring acetamide group and reduction of the A-ring nitro group, whereas the major metabolic pathway for S-4 in rats was hydrolysis on the amide bond and reduction of the A-ring nitro group. In addition, oxidative metabolites and phase II metabolites were identified in both rats and dogs. These studies demonstrate that S-4 maintains its promising pharmacokinetic properties in dogs (i.e., high oral bioavailability and linear kinetics) and is largely eliminated via hepatic metabolism by both phase I and phase II enzymes.Testosterone, an endogenous ligand for the androgen receptor, plays important and diverse physiological roles in several different organ systems, including muscle and bone (George and Wilson, 1986;Hiort, 2002). Testosterone and related anabolic steroids are used clinically as replacement therapy for primary or hypogonadotropic hypogonadism, delayed puberty, anemia, or muscle wasting conditions (Mooradian et al., 1987;Bagatell and Bremner, 1996). However, there are many disadvantages associated with testosterone and anabolic steroid therapy (Basaria and Dobs, 1999). First, current testosterone preparations can only be administered via intramuscular injections (Snyder and Lawrence, 1980). Although 17␣-alkylated androgens were developed for oral administration, they are associated with hepatic toxicity and are less efficacious; hence, they are not recommended for long-term androgen therapy (Swerdloff and Wang, 2002). Second, testosterone injections produce large fluctuations in testosterone plasma concentrations, which may lead to adverse effects such as hepatoxicity, blood pressure effects, and gynecomastia (Heywood et al., 1977;Negro-Vilar, 1999). Third, current steroidal preparations demonstrate equal anabolic and androgenic activity (i.e., they are not tissue-selective). The nonselective nature of testosterone and its derivatives, poor pharmacokinetic properties, and toxicities have led to the search for androgens with improved pro...

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Section: Discussionmentioning

confidence: 77%

In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

Perera¹,

Yin²,

Wu³

et al. 2006

Drug Metabolism and Disposition

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“…Through the use of a sulfotransferase inhibitor, pentachlorophenol, Meerman et al (48,53) have provided evidence that the predominant route to acetylated adducts is through the formation of N-sulfonyloxy-AAF. The situation regarding the nonacetylated adducts is less clear and evidence has been presented supporting N, O-acyltransferasecatalyzed formation of N-acetoxy-AF (21,54,55), direct reaction by N-hydroxy-AF (56), and AcCoA-dependent formation of N-acetoxy-AF (22).…”

Section: -Acetylaminofluorenementioning

confidence: 99%

Formation and persistence of arylamine DNA adducts in vivo.

Beland¹,

Kadlubar²

1985

Environ Health Perspect

194

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Aromatic amines are urinary bladder carcinogens in man and induce tumors at a number of sites in experimental animals including the liver, mammary gland, intestine, and bladder. In this review, the particular pathways involved in the metabolic activation of aromatic amines are considered as well as the specific DNA adducts formed in target and nontarget tissue. Particular emphasis is placed on the following compounds: 1-naphthylamine, 2-naphthylamine, 4-aminobiphenyl, 4-acetylaminobiphenyl, 4-acetylamino-4'-fluorobiphenyl, 3,2'-dimethyl-4-aminobiphenyl, 2-acetylaminofluorene, benzidine, N-methyl-4-aminoazobenzene, 4-aminoazobenzene, and 2-acetylaminophenanthrene.

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“…(60). The catalytic mechanism of these enzymes is probably different from that proposed in Figure 4A.…”

Section: Introductionmentioning

confidence: 66%

N-hydroxyarylamine O-acetyltransferase of Salmonella typhimurium: proposal for a common catalytic mechanism of arylamine acetyltransferase enzymes.

Watanabe

Igarashi

Kaminuma

et al. 1994

Environ Health Perspect

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Acetyl-CoA:N-hydroxyarylamine O-acetyltransferase is an enzyme involved in the metabolic activation of N-hydroxyarylamines derived from mutagenic and carcinogenic aromatic amines and nitroarenes. The O-acetyltransferase gene of Salmonella typhimurium has been cloned, and new Ames tester substrains highly sensitive to mutagenic aromatic amines and nitroarenes have been established in our laboratory. The nucleotide sequence of the O-acetyltransferase gene was determined.There was an open reading frame of 843 nucleotides coding for a protein with a calculated molecular weight of 32,177, which was close to the molecular weight of the O-acetyltransferase protein determined by using the maxicell technique. Only the residue of Cys69 in O-acetyltransferase of S. typhimurium and its corresponding residue (Cys68) in N-acetyltransferase of higher organisms were 69 conserved in all acetyltransferase enzymes sequenced so far. The amino acid sequence Arg-Gly-Gly-X-Cys, including the Cys , was highly conserved. A mutant O-acetyltransferase of S. typhimurium, which contained Ala69 instead of Cys69, no longer showed the activities of 0-and Nacetyltransferase. These results suggest that the Cys69 of S. typhimurium and the corresponding cysteine residues of the higher organisms are essential for the enzyme activities as an acetyl-CoA binding site. We propose a new catalytic model of acetyltransferase for S. typhimurium and the higher organisms. -Environ Health Perspect 1 02(Suppl 6): 83-89 (1994)

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Acetylation, deacetylation and acyltransfer

Cited by 74 publications

References 23 publications

In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

Formation and persistence of arylamine DNA adducts in vivo.

N-hydroxyarylamine O-acetyltransferase of Salmonella typhimurium: proposal for a common catalytic mechanism of arylamine acetyltransferase enzymes.

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