Aminoglutethimide-induced leucopenia in a mouse model: effects of metabolic and structural determinates

Coleman, Michael D.; Khalaf, L. F.; Nicholls, P. J.

doi:10.1016/j.etap.2003.08.003

Cited by 11 publications

(8 citation statements)

References 19 publications

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“…Female albino mice treated with AG (50 mg/kg/day for 21 days) were found to display a statistically lower leukocyte count (leucopenia), which included low neutrophil counts, compared to that of the control (51). This study also found no such blood dyscrasias using glutethimide, the AG congener that lacked the phenylic amine.…”

Section: Discussionsupporting

confidence: 55%

“…It has been proposed, on the basis of liver microsomal incubations, that an N-hydroxylamine metabolite was responsible for leucopenia in mice because cimetidine, a cytochrome P450 inhibitor, attenuated the leucopenic effects of AG and inhibited microsomal protein binding (51). However, SKF525A, another cytochome P450 inhibitor, did not inhibit leucopenia, and cimetidine itself has been shown to interfere with MPO activity (52).…”

Section: Discussionmentioning

confidence: 99%

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Aminoglutethimide-Induced Protein Free Radical Formation on Myeloperoxidase: A Potential Mechanism of Agranulocytosis

Siraki

Jiang

Ehrenshaft

et al. 2007

Chem. Res. Toxicol.

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Aminoglutethimide (AG) is a first-generation aromatase inhibitor used for estrogen-dependent breast cancer. Unfortunately, its use has also been associated with agranulocytosis. We have investigated the metabolism of AG by myeloperoxidase (MPO) and the formation of an MPO protein free radical. We hypothesized that AG oxidation by MPO/H 2 O 2 would produce an AG cation radical that, in the absence of a biochemical reductant, would lead to the oxidation of MPO. We utilized a novel anti-DMPO antibody to detect DMPO (5,5-dimethyl-1-pyrroline N-oxide) covalently bound to protein, which forms only by the reaction of DMPO with a protein free radical. We found that AG metabolism by MPO/H 2 O 2 induced the formation of DMPO-MPO, which was inhibited by MPO inhibitors and ascorbate. Glutethimide, a congener of AG that lacks the aromatic amine, did not cause DMPO-MPO formation, indicating the necessity of oxidation of the aniline moiety in AG. When analyzed by electron spin resonance spectroscopy, we detected a phenyl radical adduct, derived from AG, which may be involved in the free radical formation on MPO. Furthermore, we also found protein-DMPO adducts in MPO-containing, intact human promyelocytic leukemia cells (HL-60). MPO was affinity-purified from HL-60 cells treated with AG/H 2 O 2 and was found to contain DMPO. These findings were also supported by the detection of protein free radicals with electron spin resonance in the cellular cytosolic lysate. The formation of an MPO protein free radical is believed to be mediated by one of two free radical drug metabolites of AG, one of which was characterized by spin trapping with 2-methyl-2-nitrosopropane. These results are the first demonstration of MPO freeradical detection by the anti-DMPO antibody that results from drug oxidation. We propose that drugdependent free radical formation on MPO may play a role in the origin of agranulocytosis.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Aminoglutethimide-Induced Protein Free Radical Formation on Myeloperoxidase: A Potential Mechanism of Agranulocytosis

Siraki

Jiang

Ehrenshaft

et al. 2007

Chem. Res. Toxicol.

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“…It is interesting that the effect of AMG on neutrophils in rats is opposite to the agranulocytosis that is observed in some patients 6 and the leucopenia that occurs in mice. 12 However, in general, AMG patients are not monitored until blood dyscrasias arise; therefore, it is unknown whether patients experience earlier changes in their WBC differential. In the previous mouse models, leucopenia was observed as early as after 2 weeks of treatment, 12 and it may be possible that if we had continued treatment for a much longer period of time it would result in agranulocytosis.…”

Section: ■ Discussionmentioning

confidence: 99%

Effect of Aminoglutethimide on Neutrophils in Rats: Implications for Idiosyncratic Drug-Induced Blood Dyscrasias

Uetrecht

2013

Chem. Res. Toxicol.

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Aminoglutethimide (AMG) is an aromatic amine aromatase inhibitor associated with a high incidence of idiosyncratic blood dyscrasias, especially agranulocytosis. Animal models of idiosyncratic drug reactions (IDRs) represent essential tools to study these reactions; however, there is currently no valid model of idiosyncratic drug-induced agranulocytosis. Although AMG does not cause agranulocytosis in most animals or humans, drugs associated with serious IDRs generally cause a higher incidence of mild reactions that resolve despite continued treatment. Therefore, the effects of AMG on neutrophils and bone marrow in rats were studied to understand the mechanisms of more serious IDRs. An increase in peripheral blood neutrophils occurred as early as 24 h after AMG treatment with minimal changes to the total leukocyte count. Further investigation using 5-bromo-2'-deoxyuridine (BrdU) found an increased release of neutrophils from the bone marrow. Histologically, this corresponded to an increase in myeloid cells in the bone marrow, which was confirmed by differential staining with CD45 and CD71. AMG treatment stimulated an increase in colony forming unit granulocyte-macrophage and colony forming unit granulocyte ex vivo. There was also a marked increase in the number of activated neutrophils in the circulation expressing the extravasation marker CD62L. These findings indicate that AMG affects neutrophil production, release, and function. Similar effects on neutrophil kinetics in clozapine-treated rats have previously been found, and transient neutrophilia has been observed in patients taking other drugs associated with idiosyncratic agranulocytosis; therefore, the changes observed with AMG may be biomarkers to predict the risk that a drug will cause agranulocytosis.

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“…[56] Leucopenia is also reported with the use of aminoglutethimide because of formation of its cytotoxic metabolites by hepatic CYP-450 enzyme. [57] Few cases were also observed with acquired resistance following initial treatment with aromatase inhibitors due to increased oncogenic androgen receptor activity in recurrent breast cancer. [58a,58b] M A N U S C R I P T…”

Section: Figurementioning

confidence: 99%

Developing steroidal aromatase inhibitors-an effective armament to win the battle against breast cancer

Yadav

Barmade

Tamboli

et al. 2015

European Journal of Medicinal Chemistry

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Aminoglutethimide-induced leucopenia in a mouse model: effects of metabolic and structural determinates

Cited by 11 publications

References 19 publications

Aminoglutethimide-Induced Protein Free Radical Formation on Myeloperoxidase: A Potential Mechanism of Agranulocytosis

Aminoglutethimide-Induced Protein Free Radical Formation on Myeloperoxidase: A Potential Mechanism of Agranulocytosis

Effect of Aminoglutethimide on Neutrophils in Rats: Implications for Idiosyncratic Drug-Induced Blood Dyscrasias

Developing steroidal aromatase inhibitors-an effective armament to win the battle against breast cancer

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