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PubMed1998

Subchronic toxicity of human immunodeficiency virus and tuberculosis combination therapies in B6C3F1 mice.

Combination therapy with anti-HIV drugs and opportunistic infection drugs is a common practice in treatment of AIDS patients. Although toxic effects of most individual therapies are known, the toxic potential of most combination therapies has not been established. To understand the toxic consequences of combination therapies, the commonly used anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) and tuberculosis infection therapies pyrazinamide, isoniazid, and rifampicin were evaluated by 13-week gavage studies in B6C3F1 mice, either alone or AZT in combination with one of the antituberculosis drugs. The doses include AZT 100, 200, and 400; pyrazinamide 1000 and 1500; isoniazid 50, 100, and 150; and rifampicin 100, 200, and 400 mg/kg/day. AZT alone caused hematopoietic toxicity with dose-related bone marrow suppression, macrocytic anemia, and thrombocytosis. Pyrazinamide or isoniazid alone at the doses tested did not cause significant toxicity. Rifampicin alone caused hematopoietic toxicity and possibly mild hepatic toxicity. Pyrazinamide below 10 times the therapeutic dose when given with AZT did not increase the hematological toxicity of AZT. Isoniazid markedly increased the hematological toxicity of AZT and contributed to mortality at 3 to 4 times the therapeutic dose combinations. Administration of rifampicin with AZT at the calculated therapeutic doses resulted in toxicity of far greater magnitude than that caused by AZT or rifampicin alone. Combination treatment with AZT and rifampicin caused severe anemia with mortality at 2 to 4 times the therapeutic dose combinations. However, AZT did not enhance the hepatotoxicity of rifampicin. Increased hematopoietic toxicity of AZT when given in combination with the above antituberculosis drugs may be due to changes in the metabolism of AZT. Results of these studies indicate that toxicological effects of combination therapies could be considerably more severe than and different from the toxicity of individual therapies.

Animals↗

PubMed1989

The neuropathology of vigabatrin.

Vigabatrin (gamma vinyl GABA, GVG), an enzyme-activated, irreversible inhibitor of GABA transaminase, was administered orally to rats, dogs, and monkeys to observe toxicologic reactions. Myelin vacuolation of the brain was observed. The vacuolation was limited to myelinated tracts and resulted from separation of the myelin sheath at the interperiod line. There was no evidence of demyelination, axonal degeneration, or damage uolation was histologically similar to that observed in association with other drugs such as triethyltin, isoniazid, or hexachlorophene. However, the distribution is limited to the brain and is reversible upon discontinuation of therapy. Two postmortem and three operative specimens from humans have revealed no evidence of vacuolation of myelin.

Aminocaproates↗

PubMedDate not supplied

[Clinical relevance of N-acetyltransferase type 2 (NAT2) genetic polymorphism].

Polymorphic N-acetyltransferase (NAT2) is involved in the metabolism of several compounds relevant in pharmacology or toxicology, with diverse clinical consequences. Inter-ethnic variations in distribution of the acetylation phenotype are significant. The caffeine test is most often used to assess the acetylation phenotype and to identify rapid and slow acetylators. The NAT2 phenotype could account for the increased risk of certain side effects in slow acetylators treated with isoniazid (particularly peripheral neuropathies and lupus erythematosus), although therapeutic efficacy seems to be independent of the acetylation status. Hypersensibility reactions with sulfonamides (including Lyell and Stevens-Johnson syndromes) are more frequent in slow acetylators, who also show poor tolerance to sulfasalazine and dapsone. In contrast, myelotoxicity induced by amonafide is more frequent in rapid acetylators, probably because of increased production of a toxic metabolite of the drug. In carcinogenesis, NAT2 may play a protective role against bladder cancer, although studies have shown contradictory results. Slow acetylators may have a risk of developing primitive liver cancer. For lung cancer, data are not conclusive, but slow acetylation status may predispose to mesothelioma in subjects exposed to asbestos. No relation has been found between acetylation phenotype and breast cancer. Contradictory results were reported on its role in colorectal cancer. Non-smoking type 1 diabetics may be at increased risk of nephropathy if they are rapid acetylators. Parkinson's disease may be more frequent among slow acetylators, but again, data have shown contradictory results. Finally, a poor acetylator phenotype may predispose to atopic diseases.

Acetylation↗

PubMed2000

Preliminary in vitro toxicological evaluation of a series of 2-pyridylcarboxamidrazone candidate anti-tuberculosis compounds: II(1).

The in vitro toxicity of two amidrazones I [N(1)-(3-benzyloxy-4-methoxybenzylidene)-pyridine-2-carboxamidrazone] and II [N(1)-(4-benzyloxy-3-methoxybenzylidene)-pyridine-2-carboxamidrazone] and their precursors PI (3-benzyloxy-4-methoxybenzaldehyde) and PII (4-benzyloxy-3-methoxybenzaldehyde) was determined using a rat liver metabolism system with human mononuclear leucocytes (MNL) as target cells. The minimum inhibitory concentration for I and II was determined to be between 4 and 8 µg/ml against Mycobacteria fortuitum. In direct contact with human MNL at three concentrations, only II and isoniazid (INH) were significantly more toxic compared with control at 100 and 200 µM. With rat microsomes, INH and PII at 50 µM showed significant toxicity. In the two compartment system without a metabolising system, INH and II were significantly more toxic compared with control and I. In the presence of the metabolising system, INH and PI were more toxic than control and INH was more toxic compared with I. II was not significantly more toxic than control. INH caused more cell death in the presence of the metabolising system compared with its absence. Less toxic compared with INH, compound I has shown promise for future development as an antituberculosis drug.

Journal Article↗

PubMed1997

Human acetyltransferase polymorphisms.

Conjugation of primary amino and hydroxylamino groups with acetate, catalyzed by acetyl CoA-dependent arylamine acetyltransferase (NAT) enzymes, may play an important role in the intricate series of metabolic pathways that produce or prevent toxicity following exposure to homo- and heterocyclic arylamine and hydrazine xenobiotics. Two independently regulated and kinetically distinct human acetyltransferases are now known to exist, namely NAT1 and NAT2. Interindividual variation in NAT2 function is associated with the classical isoniazid acetylation polymorphism which was discovered over forty years ago. At last count, fifteen variant alleles at the NAT2 gene locus have been linked to the isoniazid 'acetylator phenotype', and each of these can be identified in population studies using specific PCR-based genotyping tests. On the other hand, NAT1 shows kinetic selectivity for compounds whose disposition is unrelated to the classical isoniazid acetylation polymorphism. NAT1 expression is also phenotypically variable in human populations, at least in part due to allelic differences at the NAT1 gene locus. Nine NAT1 variant alleles have been described to date, of which NAT1* 14 and NAT1* 15 clearly produce defective NAT1 proteins and lead to functional impairment in the metabolism of NAT1-selective substrates both in vivo and in vitro. On the other hand, it has been reported that the NAT1* 10 variant associates with elevated NAT1 activity and increased risk for cancers of the bladder and colon. Because of the important toxicologic consequences of allelic variation in NAT1 and NAT2 function for the metabolic activation of arylamine and heterocyclic amine procarcinogens, further studies are needed to improve our understanding of the extent of NAT allelic variation, to determine the functional capacity of each variant gene product, and to develop accurate methods of detecting them in population and epidemiological studies.

Acetylation↗

PubMed1977

[Toxicology of a polymerized modification of isonicotinic acid hydrazide].

The biologic side effects were studied of a polymer of isonicotinic acid hydrazide (PINH) synthesized on the basis of the copolymer vinylpyrrolidone and crotonaldehyde. The influence of dosage and conditions of administration as a functional and morphologic indicator in animals were also investigated. Threshold dosage and optimal conditions of administration in clinical practice are recommended.

Animals↗

PubMed1985

[Drug damage to the liver: role of reactive metabolites and pharmacokinetics].

Metabolism of drugs by the drug-metabolizing enzyme system usually results in the formation of less toxic substances that are readily excreted. A major advance in toxicology, however, has been the observation that the same enzyme system can also activate innocuous drugs into reactive and highly toxic metabolites. Depending on their chemical nature, these metabolites either covalently bind to cellular macromolecules, give rise to toxic oxygen species, or react with membrane lipids to form lipid peroxides. Glutathione, vitamin E and possibly other antioxidants play an important role in protecting the cell from these toxic species. Alteration of a cellular protein by a chemically reactive metabolite may lead to the formation of an antigen and result in an allergic reaction with not only hepatic, but also systemic, manifestations. The formation of toxic metabolites has been postulated in the hepatotoxicity of acetaminophen, isoniazid, halothane, erythromycin and valproic acid. With other drugs, altered pharmacokinetics in the poor metabolizer phenotype and elderly patients may predispose to toxic reactions.

Acetaminophen↗

PubMed1976

[Experimental comparison of the tuberculostatic activities of INH, INHG and INHG-Na (author's transl)].

In a comparative experimental study the glucuronic acid derivatives of isonicotinoylhydrazone (INH), isonicotinoyl-hydrazone d-glucuronic acid lactone (INHG, Gluronazid) and INH-sodium glucuronid (INHG-N-A, Gluronazid pro infusione) were shown to have the same tuberculostatic activity as INH both in vitro and in vivo. As judged by the serum inhibitory activity the serum level shows a different temporal pattern. After the administration of INHG or INHG-Na, the inhibitory activity reaches its peak later than does INH but remains in the active range essentially longer. The most substantial and, with regard to therapy, most significant difference between INHG or INHG-Na and INH lies in the varying toxicological properties. Both the oral and intravenous LD50 increase in the sequence INH, INHG and INHG-Na. The i.v. LD50 of INHG-Na exceeds the oral LD50. As compared to INH the lower toxicity permits a higher dosage of gluronazide. Thus a continuously higher serum inhibitory activity can be achieved than with a corresponding INH therapy.

Administration, Oral↗

PubMed1992

Cloned mouse N-acetyltransferases: enzymatic properties of expressed Nat-1 and Nat-2 gene products.

N-Acetylation plays an important role in the metabolism of a wide variety of hydrazine drugs and arylamine drugs and carcinogens. Humans have genetically determined differences in their N-acetyltransferase activities and are phenotypically classified as rapid or slow acetylators. Mice have a similar genetic polymorphism in N-acetyltransferase activity and have been used as models of the human polymorphism in many studies of the toxicology and carcinogenicity of arylamines. Recently, two N-acetyltransferase genes, Nat-1 and Nat-2, were cloned from rapid (C57BL/6J) and slow (A/J) acetylator mouse strains. The genomic clone encoding NAT-1 is identical in rapid and slow acetylator mouse strains, whereas the clone encoding NAT-2 differs between rapid and slow strains by a single base pair, which changes the encoded amino acid from Asn99 in the rapid acetylator strain to Ile99 in the slow acetylator strain. In this report, the N-acetylation polymorphism in mice was investigated by transiently expressing the cloned N-acetyltransferase genes in COS-1 cells. The intronless coding regions of Nat-1 and Nat-2 showed different substrate specificities; isoniazid was a preferred substrate for NAT-1, whereas p-aminobenzoic acid was preferred for NAT-2(99asn) and NAT-2(99ile). All three enzymes acetylated 2-aminofluorene, but none of them acetylated sulfamethazine. Kinetic constants determined for the expressed enzymes with 2-aminofluorene and p-aminobenzoic acid indicated that Km values were not significantly different between the enzymes, although the Vmax value of NAT-2(99asn) was consistently 2-3-fold higher than that of NAT-1 or NAT-2(99ile). Nat-1 and Nat-2 encoded mRNAs of approximately 1.4 kilobases in livers of rapid and slow acetylators. Nat-2 mRNA was more abundant in liver than Nat-1 mRNA. The abundance of Nat-2 mRNA and Nat-1 mRNA was equivalent in both rapid and slow acetylator mouse strain livers. Incubation of transfected COS-1 cell cytosols at 37 degrees showed that the time for decline of NAT activity to 50% of its initial value was 45 hr for NAT-1, 60 hr for NAT-2(99asn), and 4 hr for NAT-2(99ile). This 15-fold difference in the heat stability of the rapid and slow isoforms of NAT activity was also observed in cytosols from rapid and slow acetylator livers. Comparison of the rates of translation of the rapid and slow isoforms of NAT-2 in an in vitro system showed that NAT-2(99asn) was translated at approximately twice the rate of NAT-2(99ile).(ABSTRACT TRUNCATED AT 400 WORDS)

Acetyltransferases↗

PubMed1986

Histamine food poisoning: toxicology and clinical aspects.

Histamine poisoning can result from the ingestion of food containing unusually high levels of histamine. Fish are most commonly involved in incidents of histamine poisoning, although cheese has also been implicated on occasion. The historic involvement of tuna and mackerel in histamine poisoning led to the longtime usage of the term, scombroid fish poisoning, to describe this food-borne illness. Histamine poisoning is characterized by a short incubation period, a short duration, and symptoms resembling those associated with allergic reactions. The evidence supporting the role of histamine as the causative agent is compelling. The efficacy of antihistamine therapy, the allergic-like symptomology, and the finding of high levels of histamine in the implicated food suggest strongly that histamine is the causative agent. However, histamine ingested with spoiled fish appears to be much more toxic than histamine ingested in an aqueous solution. The presence of potentiators of histamine toxicity in the spoiled fish may account for this difference in toxicity. Several potentiators including other putrefactive amines such as putrescine and cadaverine have been identified. Pharmacologic potentiators may also exist; aminoguanidine and isoniazid are examples. The mechanism of action of these potentiators appears to be the inhibition of intestinal histamine-metabolizing enzymes. This enzyme inhibition causes a decrease in histamine detoxification in the intestinal mucosa and results in increased intestinal uptake and urinary excretion of unmetabolized histamine.

Animals↗

PubMed1990

Acetylation.

UNLABELLED: The human acetylation polymorphism has been known for more than three decades since its discovery during the metabolic investigation of the antituberculous hydrazine drug, isoniazid. The trait was originally known as the "isoniazid acetylation polymorphism" but is now usually abbreviated to the "acetylation polymorphism" because the acetylation of numerous hydrazine and arylamine drugs and other chemicals are subject to this trait. A. Individuals phenotype as "slow" acetylators, homozygous for the slow acetylator gene, or "rapid" acetylators either heterozygous or homozygous for the rapid acetylator gene. Differences in individual acetylating capacity are ascribed to differences in the activities of the arylamine acetylating enzymes (isozymic N-acetyltransferase variants) of the liver, intestinal mucosa and certain other tissues. The chromosomal locus of the human gene has not been determined, but linkage analysis in mice indicates that the N-acetyltransferase gene is closely linked to Esterase-1 on mouse chromosome 8. RECOMMENDATION: 1) That the chromosomal locus of the human acetylator gene(s) be determined. B. The acetylator phenotype is a lifelong, stable characteristic of the individual that can be determined by procedures using any of several test agents (eg, caffeine, isoniazid, sulfamethazine, sulfapyridine). All suitable test agents discriminate rapid and slow acetylator phenotypes, whereas caffeine enables homozygous and heterozygous rapid acetylators to be discriminated from each other and from slow acetylators. These procedures can be used with confidence to determine the acetylator status of healthy adults and children but caution is necessary in interpreting this information for infants, in altered physiologic states and in the presence of certain diseases and environmental substances. RECOMMENDATIONs: 1) That investigators should strongly consider the use of the caffeine test for acetylator phenotype determination in human epidemiologic studies of acetylation because of its advantages over other test agents that are available. 2) That efforts to determine the structure of the acetylator genes responsible for the human acetylator polymorphism, and to determine the genes responsible for the hereditary acetylator polymorphisms in animal models for the human trait be continued apace with efforts on the human system. 3) That an improved test to determine the acetylator status utilizing that information and current molecular biology approaches and techniques applied to tissues that are readily available in human subjects (eg, leukocytes) be developed at a high priority. C. The hereditary acetylator status of individuals provides valuable information about their therapeutic, pharmacologic and toxicologic responses and is a prognosticator of unusual susceptibility to toxicity from drugs widely used for the treatment of diverse diseases.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylation↗

PubMed1991

Toxicological study of pyridoxal isonicotinoyl hydrazone: acute and subchronic toxicity.

Pyridoxal isonicotinoyl hydrazone (PIH) is a highly effective iron chelator. Acute toxicity testing was performed in mice and rats of both sexes, with 10 mice or rats/sex/group. The LD50 values of PIH in both species were 5 and 1 g/kg given orally and intraperitoneally, respectively. Microscopic examination of tissues from the highest oral dose (6 g/kg) animals that survived 7 days revealed fatty degeneration in the liver. Subchronic toxicity was tested in rats of both sexes, with 8 males and 8 females/group. PIH doses of 100, 400 and 800 mg/kg were given orally for 90 consecutive days. Water was given to the control group. Hematocrit and blood chemistries were analysed at weeks 3, 6, 10 and 13. There were no changes in hematocrit and BUN. PIH at doses of 800 mg/kg caused a significant increase in serum alkaline phosphatase and transaminase levels at week 13. Microscopic examination showed hepatic degeneration in a dose-related fashion. Vascular congestion of the kidney and spleen was also found. No histopathological changes were detected in sections from the stomach and intestine.

Administration, Oral↗