Involvement of leukocytes in the oxygenation and chlorination reaction of phenylbutazone

Ichihara, Shigeyasu; Tomisawa, Hiroki; Fukazawa, Hideo; Tateishi, Mitsuru; Joly, Raymond; Heintz, R.

doi:10.1016/0006-2952(86)90007-9

Cited by 35 publications

(11 citation statements)

References 10 publications

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“…Thus, the presence of a hydroxyl group at the medial carbon of the 1,3-diketone moiety in 4-OH-PBZ prevented the reaction with CO 3 •– . Our finding is consistent with other studies that showed the necessity of the medial carbon atom of a 1,3-diketone moiety in scavenging reactive oxygen species. , …”

Section: Discussionsupporting

confidence: 94%

“…This suggests that an interaction of PBZ with CO 3 •– , led to the oxidation of PBZ to form 4-OH-PBZ. This finding is consistent with those of other investigations that showed that oxidation of PBZ by leukocytes (myeloperoxidase) resulted in the formation of different metabolites, including 4-OH-PBZ, 4-hydroperoxyphenylbutazone, and 4-chlorophenylbutazone . The final evidence for the metabolic scheme (Scheme ) was derived from LC/MS studies that confirmed the presence of 4-hydroperoxy-PBZ as well as 4-OH-PBZ, which have been reported as products generated from prostaglandin H synthase peroxidase activity…”

Section: Discussionsupporting

confidence: 91%

“…For example, horseradish peroxidase (HRP, a plant peroxidase) can catalyze the formation of PBZ radicals that are reported to inactivate α 1 -antiproteinase, cholinesterase, and creatine kinase. − Ichihara et al emphasized that PBZ is likely to act as a scavenger against reactive oxygen species because it possesses a 1,3-diketone moiety in its structure. This suggests that there may yet be other pathways to generate PBZ radicals. , …”

Section: Introductionmentioning

confidence: 99%

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Phenylbutazone Oxidation via Cu,Zn-SOD Peroxidase Activity: An EPR Study

Aljuhani

Whittal²,

Khan³

et al. 2015

Chem. Res. Toxicol.

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We investigated the effect of Cu,Zn-superoxide dismutase (Cu,Zn-SOD)-peroxidase activity on the oxidation of the nonsteroidal anti-inflammatory drug phenylbutazone (PBZ). We utilized electron paramagnetic resonance (EPR) spectroscopy to detect free radical intermediates of PBZ, UV-vis spectrophotometry to monitor PBZ oxidation, oxygen analysis to determine the involvement of C-centered radicals, and LC/MS to determine the resulting metabolites. Using EPR spectroscopy and spin-trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), we found that the spin adduct of CO3(•-) (DMPO/(•)OH) was attenuated with increasing PBZ concentrations. The resulting PBZ radical, which was assigned as a carbon-centered radical based on computer simulation of hyperfine splitting constants, was trapped by both DMPO and MNP spin traps. Similar to Cu,Zn-SOD-peroxidase activity, an identical PBZ carbon-centered radical was also detected with the presence of both myeloperoxidase (MPO/H2O2) and horseradish peroxidase (HRP/H2O2). Oxygen analysis revealed depletion in oxygen levels when PBZ was oxidized by SOD peroxidase-activity, further supporting carbon radical formation. In addition, UV-vis spectra showed that the λmax for PBZ (λ = 260 nm) declined in intensity and shifted to a new peak that was similar to the spectrum for 4-hydroxy-PBZ when oxidized by Cu,Zn-SOD-peroxidase activity. LC/MS evidence supported the formation of 4-hydroxy-PBZ when compared to that of a standard, and 4-hydroperoxy-PBZ was also detected in significant yield. These findings together indicate that the carbonate radical, a product of SOD peroxidase activity, appears to play a role in PBZ metabolism. Interestingly, these results are similar to findings from heme peroxidase enzymes, and the context of this metabolic pathway is discussed in terms of a mechanism for PBZ-induced toxicity.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phenylbutazone Oxidation via Cu,Zn-SOD Peroxidase Activity: An EPR Study

Aljuhani

Whittal²,

Khan³

et al. 2015

Chem. Res. Toxicol.

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“…Our studies demonstrate that PMNs can metabolize amodiaquine to proteinarylating derivatives [26]. This can be rationalized in terms of the drug's oxidation by reactive oxygen spe cies and other oxidants generated upon activation of the cells [27], PMN-derived oxidants have been re ported to transform a variety of chemicals [28], in cluding drugs [14,29], to both stable and chemically reactive metabolites; catalysis by myeloperoxidase is frequently implicated [30], Since bone marrow cells contain appreciable amounts of myeloperoxidase [31], and if amodiaquine, like chloroquine [32], might become concentrated in lysosomes, myeloperoxidase catalysis represents a route by which AQQI may be formed locally in vivo, inducing either a direct cyto toxicity or an immune response. The immune system is capable of responding to the very low levels of im munogen that may be produced by this pathway.…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity of Amodiaquine in the Rat

Clarke

Maggs

Kitteringham

et al. 1990

Int Arch Allergy Immunol

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Amodiaquine is an antimalarial drug that has been associated with adverse reactions which may be immune mediated. Specific IgG anti-amodiaquine antibodies were detected after administration of the drug to rats (269 μmol/kg for 4 days), using an enzyme-linked immunosorbent assay employing amodiaquine conjugated to metallothionein as an antigen. A positive immune response was observed regardless of the route of administration, but the magnitude of the response in terms of antibody titre was in the order intraperitoneal administration > intramuscular administration > oral administration. Hapten inhibition experiments with structurally related drugs defined the specificity of the antibody which appears to recognize a conjugate of amodiaquine quinone imine and cysteine residues present in protein. Amodiaquine was converted to a protein-reactive species by activated human polymorphonuclear leucocytes in vitro, and this may provide a mechanism for immunogen formation in vivo. A humoral immune response was observed with doses of amodiaquine that did not produce either direct hepatotoxicity or leucopenia. Thus an animal model has been developed with which to investigate the toxicological consequences of amodiaquine immunogenicity.

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“…Unlike the cytochrome P-450 system, hypochlorous acid cannot oxidise most carbon-hydrogen bonds, although there are exceptions such as phenylbutazone (Ichihara et al 1986). However, the number of neutrophils activated at anyone time is likely to be low, and once a neutrophil is maximally activated it probably has a rather short life span.…”

Section: Drug Metabolism By Neutrophilsmentioning

confidence: 99%

Metabolism of Clozapine† by Neutrophils

Uetrecht

1992

Drug Safety

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Many types of adverse drug reactions appear to involve reactive metabolites which, by their very nature, usually have short biological half-lives. Therefore, reactive metabolites formed by neutrophils, or neutrophil precursors in the bone marrow, would seem more likely to be responsible for drug-induced agranulocytosis than metabolites formed in the liver. We have found that several drugs associated with a relatively high incidence of drug-induced agranulocytosis are metabolised by activated neutrophils to chemically reactive metabolites. In preliminary experiments with clozapine, we found that clozapine was metabolised by neutrophils. It also reacted with hypochlorous acid, the principal oxidant generated by neutrophils, to form a reactive intermediate. This intermediate has a half-life of I minute in buffer, but reacts very rapidly with glutathione. We believe that this intermediate is a nitrenium ion. Such a metabolite could be responsible for clozapine-induced agranulocytosis, either by direct toxicity or through an immunemediated mechanism.

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Involvement of leukocytes in the oxygenation and chlorination reaction of phenylbutazone

Cited by 35 publications

References 10 publications

Phenylbutazone Oxidation via Cu,Zn-SOD Peroxidase Activity: An EPR Study

Phenylbutazone Oxidation via Cu,Zn-SOD Peroxidase Activity: An EPR Study

Immunogenicity of Amodiaquine in the Rat

Metabolism of Clozapine† by Neutrophils

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