Relationship between nucleic acid adduct formation and deacylation of arylhydroxamic acids

Glowinski, Irene B.; Savage, Laura; Lee, Mei‐Sie; King, Charles M.

doi:10.1093/carcin/4.1.67

Cited by 22 publications

(16 citation statements)

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“…The N-terminal amino acid sequence of GHA deacetylase (Table 3) is similar to those reported for guinea-pig and rat carboxylesterases [36]. Several kinds of deacetylase activity in guinea-pig liver microsomes have been reported [29,36,[42][43][44][45][46][47][48][49][50]. Among these enzymes, the following are thought to resemble GHA deacetylase : the deacetylase of N-hydroxy-N-2-fluorenylacetamide with a molecular mass of 200 kDa [29], and GPH1, a trimeric protein of pI 5.3 composed of subunits with a molecular mass of 57 kDa [36].…”

Section: Discussionsupporting

confidence: 72%

Purification and characterization of guinea-pig liver microsomal deacetylase involved in the deacetylation of the O-glucoside of N-hydroxyacetanilide

Suzuki-Kurasaki

Yoshioka

Uematsu

1997

Biochemical Journal

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A microsomal deacetylase that catalyses the deacetylation of the O-glucoside of N-hydroxyacetanilide (GHA) was purified from guinea-pig liver. The activity was located exclusively in the microsomes and not detected in the cytosol. The purified GHA deacetylase was a trimeric protein with a molecular mass of 160±10 (S.D.) kDa composed of subunits of 53±2 kDa; its pI was 4.7. The N-terminal amino acid sequence of GHA deacetylase was similar to those reported for guinea-pig and rat liver microsomal carboxylesterases. The GHA deacetylase showed a comparable hydrolytic activity towards p-nitrophenyl acetate (PNPA), although the activities towards N-hydroxyacetanilide, acetanilide and some endogenous acylated compounds were very low or not detectable. The deacetylase activity towards GHA was inhibited by organophosphates but not by p-chloromercuribenzoate, suggesting that GHA deacetylase can be classified as a B-esterase. The enzyme exhibited a positive homotropic co-operativity towards GHA. The values of the Hill coefficient, the half-saturating concentration ([S]0.5) for GHA, and Vmax were 1.59±0.03, 5.51±0.07 mM and 32.5±1.4 μmol/min per mg respectively, at the optimum pH of 8.5. The bell-shaped pH dependence of the Vmax/[S]0.5 profile indicated pKa values attributed to histidine and lysine residues. The study of stoichiometric inhibition by di-isopropyl fluorophosphate and kinetic analysis with the Monod–Wyman–Changeux model suggests that GHA deacetylase has six substrate binding sites and three catalytically essential serine residues per enzyme molecule.

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Section: Discussionsupporting

confidence: 72%

Purification and characterization of guinea-pig liver microsomal deacetylase involved in the deacetylation of the O-glucoside of N-hydroxyacetanilide

Suzuki-Kurasaki

Yoshioka

Uematsu

1997

Biochemical Journal

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“…Similar sex differences have been observed in the mutagenic activation of AAF by mouse kidney microsomes (17). Studies to determine if AHAT activity was genetically controlled in a manner similar to that for NAT in inbred mice revealed that this was not the case and that only marginal AHAT activity was detected (18).…”

Section: Genetic Regulationmentioning

confidence: 99%

“…AHAT is widely distributed, as detected by nu- (1,18,26,27). Mono-, di-and tricyclic arylhydroxamic acids, including derivatives of phenacetin, naphthalene, biphenyl, stilbene, fluorene and phenanthrene, can also serve as substrates such as phenacetin, the rats of adduct formation are considerably less than those for N-acetyltransfer as measured by the Booth assay (29).…”

Section: No*acyltransfermentioning

confidence: 99%

“…Microsomal AHAT Recent observations have disclosed that liver microsomes from a number of species have the ability to generate nucleic acid adducts on incubation with arylhydroxamic acids (Table 5) (1,18). This activity yields arylamine-substituted guanine derivatives at carbon-8 without retention of the acyl group to give the same product as that produced by the cytosolic acyltransferases.…”

Section: No*acyltransfermentioning

confidence: 99%

“…The AHAT activities were detected by assay of nucleic acid adduct formation on incubation with either the N-forymylated (F) or N-acetylated (Ac) N-2-fluorenylhydroxylamine. Type I and II AHAT are inhibited by diethyl-p-nitrophenylphosphate; Type III is resistant to this organophosphate (1,18).…”

Section: No*acyltransfermentioning

confidence: 99%

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Acetylation, deacetylation and acyltransfer

King¹,

Glowinski²

1983

Environ Health Perspect

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N -Substituted aromatic compounds can be metabolized in most species to N -acetylated derivatives that are themselves subject to further enzymatic transformations, including hydrolysis and N,O -acyltransfer. These proceses can either potentiate or ameliorate the biological responses to these N -substituted derivatives. Decreasing the levels of metabolites, such as arylhydroxylamines may, in some systems, reduce the probability of eliciting adverse biological effects. In others, arylhydroxamic acids produced by the acetylation of arylhydroxylamines may increase their potential for metabolic activation by N,O -acyltransfer. In the rabbit, rat and perhaps other species, the acetyl CoA-dependent N -acetyltransferase is also capable of activating arylhydroxamic acids by N-O -acyltransfer. These cytosolic organotriphosphate ester-resistant enzymes can utilize arylhydroxamic acid as a donor of the acetyl moiety in the acetyl transferase reaction and apparently are capable of activating arylhydroxamic acids because of their ability to O -acetylate the arylhydroxlamine. In mice, N -acetyltransferase and N,O -acetyltransferase seem not to exhibit this relationship. Enzymes from the microsomes of a number of species are also capable of activating arylhydroxamic acids. The particulate-bound enzymes are organotriphosphate ester-sensitive deacylases that are unable to form nucleic acid adducts on incubation with N -methoxy- N -acetylaminoarenes, substrates that are not capable of activation by N,O -acyltransfer. Thus, depending on the specificity of the enzymes involved, N -substituted aromatic compounds may be activated by N,O -acyltransfer during both the acetylation and deacylation process. The influence of this activation in the carcinogenic process is the object of continuing investigation.

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Microsomal deacetylation of ring-hydroxylated 2-(acetylamino)fluorene isomers: Effect of ring position and molecular mechanics considerations

Castañeda‐Acosta

Bounds

Winston

1999

J. Biochem. Mol. Toxicol.

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Relationship between nucleic acid adduct formation and deacylation of arylhydroxamic acids

Cited by 22 publications

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Purification and characterization of guinea-pig liver microsomal deacetylase involved in the deacetylation of the O-glucoside of N-hydroxyacetanilide

Purification and characterization of guinea-pig liver microsomal deacetylase involved in the deacetylation of the O-glucoside of N-hydroxyacetanilide

Acetylation, deacetylation and acyltransfer

Microsomal deacetylation of ring-hydroxylated 2-(acetylamino)fluorene isomers: Effect of ring position and molecular mechanics considerations

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