Acetylating, Deacetylating and Amino Acid Conjugating Enzymes

Weber, Wendell W.

doi:10.1007/978-3-642-65177-9_33

Cited by 16 publications

(5 citation statements)

References 54 publications

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“…Numerous studies have shown that the metabolism of isoniazid is noninducible, that there are large differences between individuals in the rates at which isoniazid is metabolized, and that the great majority of individuals can be clearly characterized as being either slow or rapid metabolizers of the drug.v- 41,48,67 The range of isoniazid serum half-lives obtained by Tiitinen'" after intravenous doses of 5 mg/kg isoniazid to over 300 subjects in Finland is illustrated in Fig. 1.…”

Section: The Metabolism Of Isoniazid In Manmentioning

confidence: 99%

Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis

Ellard

1976

Clin Pharma and Therapeutics

121

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Isoniazid is the most effective and widely used antituberculosis drug. The metabolism of isoniazid is noninducible and the primary metabolie route determining the rate at which isoniazid is eliminated from the body is acetylation. There are large differences between individuals in the rates at which isoniazid and certain other hydrazides and some sulfonamides are acetylated. The acetylation of isoniazid is inherited in a simple Mendelian fashion, individuals being either slow, heterozygous rapid, or homozygous rapid acetylators . Improved methods of discriminating between the different phenotypes have recently been described that are also more convenient to use. The proportion of slow acetylators among Japanese and Eskimos is about 10%; among Chinese about 20%; among Caucasians, Negroes, and South Indians about 60%. The results of aseries of meticulously controlled clinical trials carried out in India, East Africa, Hong Kong, Singapore, Czechoslovakia, and Britain have shown the isoniazid acetylator status of tuberculosis patients treated with isoniazid‐containing regimens is of no prognostic significance when treatment is given on a daily basis. It may, however, be of significance when twice‐weekly regimens are employed, especially in circumstances in which only a short period of initial daily chemotherapy is given, and where the companion drug employed during the twice‐weekly continuation phase is relatively weak. The acetylator phenotype is, however, extremely important in once‐weekly treatment, rapid acetylators always having fared considerably worse than slow acetylators on all the regimens evaluated so far. Experimental studies of the action of isoniazid against Mycobacterium tuberculosis in vitro and in vivo have enabled these findings to be understood.

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Section: The Metabolism Of Isoniazid In Manmentioning

confidence: 99%

Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis

Ellard

1976

Clin Pharma and Therapeutics

121

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“…1 and 2), it can be seen that in 'slow' acetylators, the maximum concentration is lower than in 'fast' acetylators. Different plasma concentrations and a similar elimination half-life of metabolite and parent compound indicate that there may be 1 enzyme at different concentrations in 'sloW' and 'fast' acetylators (Weber and Cohen, 1968;Weber, 1971;Hearse and Weber, 1973). Another indication is obtained from the half-life of the residual curve of the percentage N 4 -acetyl derivative.…”

Section: Discussionmentioning

confidence: 94%

Determination of the Acetylator Phenotype and Pharmacokinetics of Some Sulphonamides in Man

Vree

O'Reilly

Damsma

et al. 1980

Clinical Pharmacokinetics

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The pharmacokinetics of sulphamethizole, sulphamethoxazole, sulphadiazine, sulphapyridine and sulphadimidine have been studied in man. Renal clearance values of the metabolite N4-acetylsulphonamide are 6 to 20 times higher than those of the corresponding parent compound. The renal clearance of sulphonamides is dependent on the urine flow. N4-Acetylsulphonamide concentration-time profiles for plasma and urine have been constructed for the sulphonamides. The percentage N4-acetylsulphonamide-time profiles for plasma are excellent tools for establishing the acetylator phenotype, while those constructed from urine samples are less useful. Evidence is obtained that sulphadimidine is metabolically processes by 2 different isoenzymes, while sulphadiazine, sulphapyridine and sulphamethoxazole are processes by 1 acetylating isoenzyme. Sulphamethizole is acetylated to very little extent.

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“…For example, the major metabolic pathway of the arylamine-based pesticide propanil in microsomal incubations was acylamidasecatalysed hydrolysis to 3,4-dichloroaniline (McMillan et al 1990a, Singleton andM u rphy 1973). The enzymes responsible for the catalysis of the deacetylatio n belong to the general class of arylacylamide amidohydrolases (EC 3.5.1.13) and are usually referred to as arylamidases or deacetylases (Weber 1985).…”

Section: Discussionmentioning

confidence: 99%

Biomonitoring of arylamines: haemoglobin adducts of aniline derivatives

Beyerbach

Sabbioni²

1999

Biomarkers

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Aromatic amines are important intermediates in industrial manufacturing. They are used in a large number of products, such as pesticides, dyes, plastics and pharmaceuticals. The parent arylamines can be metabolically released from these arylamine-based compounds and form DNA and protein adducts after N-oxidation to N-hydroxy arylamines. Aromatic amine derivatives, including the industrial intermediates acetoacetanilide, acetoacet-m-xylidide and N-ethylaniline, were examined for their ability to form Hb adducts in rats as potential biomarkers of exposure. The haemoglobin binding indices (HBI=binding [mmol mol(-1) Hb]/dose [mmol kg(-1) body weight]) of the arylamines were determined 24 h after oral administration to female Wistar rats. The precipitated haemoglobin was dissolved in 0.1 M sodium hydroxide in the presence of internal standards. After hexane extraction the released arylamines were analysed by gas chromatography-mass spectrometry (GC-MS). For aniline released from acetoacetanilide an HBI of 15 and for 2,4-dimethylaniline released from acetoacet-m-xylidide an HBI of 0.129 were determined. The HBIof aniline released from N-ethylaniline was 45.

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Acetylating, Deacetylating and Amino Acid Conjugating Enzymes

Cited by 16 publications

References 54 publications

Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis

Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis

Determination of the Acetylator Phenotype and Pharmacokinetics of Some Sulphonamides in Man

Biomonitoring of arylamines: haemoglobin adducts of aniline derivatives

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