Aerobic nitroreduction of dehydrochloramphenicol by bone marrow

Isildar, M.; Abou-Khalil, Wafa H.; Jiménez, Joaquín J.; Abou‐Khalil, Samir; Yunis, Adel A.

doi:10.1016/0041-008x(88)90272-4

Cited by 19 publications

(6 citation statements)

References 12 publications

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“…It has been suggested 4 that the reduction of the p-NO 2 group on the benzene ring (Figure 1) leads to the production of nitroso-and hydroxylamino-metabolites capable of causing DNA strand breakage and initiation of the aplastic anaemia seen as a rare complication of therapy with CAP. 5 Attempts to demonstrate aerobic nitro-reduction of CAP to its amine derivative by human tissue systems have proved largely unsuccessful, 6 although the antibiotic is readily reduced under anaerobic conditions. 4 The toxic intermediates of CAP nitro-reduction, the nitroso-and hydroxylami-no-derivatives, are unstable in blood 7 and thus unlikely to survive long enough to reach their target in the bone marrow.…”

Section: Introductionmentioning

confidence: 99%

The role of nitro-reduction and nitric oxide in the toxicity of chloramphenicol

Holt

Bajoria

1999

Hum Exp Toxicol

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1 Recent work on the toxicology of chloramphenicol suggests that its propensity to cause damage to the blood forming organs may be related to its potential for nitro-reduction and the subsequent production of nitric oxide. 2 In this study both aerobic and anaerobic nitro-reduction of chloramphenicol by human foetal and neonatal liver results in the production of the amine derivative. However intermediates of the reaction nitroso-or glutathionesulphinamido-chloramphenicol could not be detected by hplc. 3 Perfusion of chloramphenicol through isolated lobules of human placentae caused a decrease in blood pressure at a time which coincided with a peak of nitric oxide production. However, although the pressure drop could be reversed by an inhibitor of nitric oxide synthetase, the nitric oxide profile remained the same. 4 These observations suggest that involvement of the para-nitro group of chloramphenicol could cause both hemotoxicity and hypotension in susceptible individuals.

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Section: Introductionmentioning

confidence: 99%

The role of nitro-reduction and nitric oxide in the toxicity of chloramphenicol

Holt

Bajoria

1999

Hum Exp Toxicol

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“…However, additional to bacterial biotransformation nitroso compounds might be formed from DH-CAP in bone marrow cells, as it has been shown that these cells as well as liver cells possess a specific nitrobenzene reductase which is able to nitroreduce DH-CAP easily (Abou-Khalil et al, 1985). Thus, as the direct conversion of CAP into NO-CAP seems to be impossible in bone marrow cells under aerobic conditions (Isildar et al, 1988a) it is likely that DH-CAP is the stable intermediate (Abou-Khalil et al, 1988) being the pre-requisite for nitroreduction in bone marrow cells.…”

Section: Discussionmentioning

confidence: 81%

Pharmacokinetic and toxicological aspects of the medication of beef‐type calves with an oral formulation of chloramphenicol palmitate

Gaßner

Wuethrich

1994

Vet Pharm & Therapeutics

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Chloramphenicol (CAP) plasma levels were determined after oral administration of four doses of CAP palmitate (each dose corresponding to CAP 25 mg/kg/12 h) to four ruminating beef-type calves. Steady-state plasma concentrations of CAP were reached after the fourth oral dose and varied between 5 and 6 micrograms/ml. Half-life of elimination of CAP was 4.5 h. In addition to CAP, dehydrochloramphenicol (DH-CAP), a metabolite of chloramphenicol, was detected in plasma at concentrations between 3 and 7 ng/ml. DH-CAP is known to be produced from CAP by intestinal bacteria. This is significant since DH-CAP is suspected of being involved in the development of fatal aplastic anaemia, which occurs in man after exposure to CAP. Thus, it cannot be excluded that DH-CAP residues may occur in edible tissues. A risk arising from DH-CAP can neither be excluded for the animals being treated with CAP nor for consumers.

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“…White cells at relatively early stages of human neutrophil maturation, such as promyelocytes, contain considerable amounts of myeloperoxidase [Bainton et al, 19711 and are therefore capable of oxidising dapsone. A number of other compounds have been shown to be oxidised by human bone marrow, including dehydrochloramphenicol, 2,2,2 trifluoroethanol and catechol [Isildar et al, 1988;Fraser and Kaminsky, 1988;Bhat et al, 19881. In addition, a number of cytochrome P450 enzymes have been characterised in rabbit bone marrow, including P450 I1 El and IAI [Schnier et al, 19891. It is apparent that bone marrow is capable of a range of oxidation reactions, mediated by either P450 or peroxidase enzymes.…”

Section: Toxicitymentioning

confidence: 99%

Use of a metabolic inhibitor to reduce dapsone‐dependent haematological toxicity

Coleman

Tingle

1992

Drug Development Research

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Coleman, M.D., and M.D. Tingle: Use of a metabolic inhibitor to reduce dapsone-dependent haematological toxicity. Drug Dev. Res. 25:l-16, 1992.Aside from its established use as an antileprotic and anti-inflammatory drug, dapsone is also effective in the therapy of Pneurnocystis carinii pneumonia. Unfortunately, its use is often limited by its dose-dependent toxicity, such as methaemoglobinaemia and haemolysis; the latter condition occurs most frequently in gIucose-6-dehydrogenase deficient individuals. It is also responsible for occasional life-threatening disorders such as agranulocytosis. Dapsone may undergo acetylation, but its toxicity is due to the product of its oxidative metabolism, dapsone hydroxylamine. This is generated in man by the constitutive hepatic cytochrome P450 enzyme IIIA4. Studies in the rat revealed that dapsone-dependent methaemoglobinaemia could be greatly diminished by the co-administration of metabolic inhibitors. In the isolated perfused rat liver, dapsone hydroxylamine levels and hence methaemoglobin formation fell significantly in the presence of cimetidine. In addition, the clearance of the parent drug was retarded, and perfusate concentrations of monoacetyl dapsone increased. The protective effect of cimetidine also reduced methaemoglobin formation in the whole rat during the chronic administration of dapsone. Incubation of dapsone in a two-compartment in vitro system using human tissues in the presence of cimetidine or ketoconazole resulted in a decrease in methaemoglobin formation in all the human livers tested. Although cimetidine was only effective if incubated with microsomes and NADPH prior to the addition of dapsone. Administration of cimetidine (3 x 400 mg daily) to volunteers 3 days prior to and 4 days post administration of a single dose of 100 mg dapsone caused drug concentrations to increase by almost 30%. There was a marked fall in peak methaemoglobin levels and the percentage of the dose excreted in urine as dapsone hydroxylamine N-glucuronide was reduced by almost one third. During high dose dapsone therapy it may be possible that the co-administration of cimetidine might reduce toxicity while maintaining drug efficacy.

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Aerobic nitroreduction of dehydrochloramphenicol by bone marrow

Cited by 19 publications

References 12 publications

The role of nitro-reduction and nitric oxide in the toxicity of chloramphenicol

The role of nitro-reduction and nitric oxide in the toxicity of chloramphenicol

Pharmacokinetic and toxicological aspects of the medication of beef‐type calves with an oral formulation of chloramphenicol palmitate

Use of a metabolic inhibitor to reduce dapsone‐dependent haematological toxicity

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