Bioactivation to an aldehyde metabolite—Possible role in the onset of toxicity induced by the anti-HIV drug abacavir

doi:10.1016/j.toxlet.2013.10.036

Toxicology Letters

Volume 224, Issue 3, 30 January 2014, Pages 416-423

https://doi.org/10.1016/j.toxlet.2013.10.036 Get rights and content

Abstract

Aldehydes are highly reactive molecules, which can be generated during numerous physiological processes, including the biotransformation of drugs. Several non-P450 enzymes participate in their metabolism albeit alcohol dehydrogenase and aldehyde dehydrogenase are the ones most frequently involved in this process. Endogenous and exogenous aldehydes have been strongly implicated in multiple human pathologies. Their ability to react with biomacromolecules (e.g. proteins) yielding covalent adducts is suggested to be the common primary mechanism underlying the toxicity of these reactive species.

Abacavir is one of the options for combined anti-HIV therapy. Although individual susceptibilities to adverse effects differ among patients, abacavir is associated with idiosyncratic hypersensitivity drug reactions and an increased risk of cardiac dysfunction. This review highlights the current knowledge on abacavir metabolism and discusses the potential role of bioactivation to an aldehyde metabolite, capable of forming protein adducts, in the onset of abacavir-induced toxic outcomes.

Introduction

Human immunodeficiency virus (HIV) infection is currently considered a chronic disease in developed countries. The drastic change in HIV prognosis that occurred in the last two decades is credited to the indubitable benefits of combined antiretroviral therapy (cART). However, in light of the current therapeutic options, once the HIV-infected patient starts cART the treatment will persist throughout life. Consequently, the choice of appropriate long-term treatment options for an aging population has become a new challenge.

Contrasting with acute cART-induced toxic events, the long-term toxic outcomes remain mostly unknown. However, in a scenario of lifelong cART usage, the potential increase in the incidence of such adverse effects cannot be neglected. In fact, the expected negative impact on clinical outcomes, which will ultimately affect the life quality and expectancy of HIV patients, is an emerging concern. Decreased adherence to cART and a need for additional clinical interventions are expected to be further consequences of these long-term toxic effects.

Currently, first-line cART is always composed of at least three drugs, two of which are nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). Abacavir (ABC, Scheme 1) is one of the anti-HIV drugs of this class and ABC-based regimens have a significant role in HIV-treatment guidelines, due to the antiretroviral efficacy of the drug and its availability in one-pill fixed-dose combinations (Thompson et al., 2010, EACS, 2012). Consequently, the widespread prescription of this drug prompts concerns about ABC-induced toxic outcomes.

Section snippets

Abacavir pharmacology

ABC is a 2′-deoxyguanosine nucleoside analogue with anti-HIV type-1 and type-2 activities (Daluge et al., 1997, Hervey and Perry, 2000, Saag et al., 2008). The drug is recommended to both adults and children and is commercially available as ABC sulphate alone (Ziagen^®) or as part of two-drug (ABC/lamivudine (3TC; Kivexa^®) and three-drug (ABC/3TC/zidovudine; Trizivir^®) pill combinations. The recommended oral dose of ABC for adults is 600 mg daily, administered either as 300 mg twice daily or 600 mg

The role of the bioactivation to a conjugated aldehyde in the onset of abacavir-induced toxic events

Drug bioactivation is a frequent event in the onset of drug-induced toxicity (Uetrecht, 2006, Srivastava et al., 2010). Concurrently with excretable metabolites, biotransformation pathways can also be responsible for the formation of reactive (primarily electrophilic) species, capable of reacting with biomacromolecules and afford covalent adducts (e.g. with proteins), which may elicit direct cell toxicity and/or trigger an immune response. In particular, the toxicological significance of

Conclusions

The current evidence is consistent with a role of ABC bioactivation to ABC-derived aldehydes as an important factor underlying both acute and long-term toxic outcomes of this antiretroviral drug.

The recognition of a genetic association in the ABC-induced HSR allowed an efficient reduction of acute toxic events, through the implementation of a prospective screening test to identify carriers of the high risk allele. However, the fact that this test has a positive predictive value of 50% may lead

Role of the funding source

This work was supported in part by Fundação para a Ciência e a Tecnologia, through grants PTDC/SAU-TOX/111663/2009, PTDC/QUI-QUI/113910/2009 and PEst-OE/QUI/UI0100/2013. NM Grilo also thanks FCT for a PhD fellowship (SFRH/BD/86791/2012).

Conflicts of interest

The authors declare no conflict of interest.

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Mini reviewBioactivation to an aldehyde metabolite—Possible role in the onset of toxicity induced by the anti-HIV drug abacavir

Abstract

Introduction

Section snippets

Abacavir pharmacology

The role of the bioactivation to a conjugated aldehyde in the onset of abacavir-induced toxic events

Conclusions

Role of the funding source

Conflicts of interest

Trends Endocrinol. Metab.

Lancet

Immunity

Biochem. Biophys. Res. Commun.

Toxicology

Clin. Ther.

Free Radic. Biol. Med.

Toxicol. Lett.

Transl. Res.

J. Biol. Chem.

Chem. Biol. Interact.

Free Radic. Biol. Med.

Biochem. Biophys. Res. Commun.

Free Radic. Biol. Med.

Drug Metab. Pharmacokinet.

J. Allergy Clin. Immunol.

Chem. Biol. Interact.

Biomed. Pharmacother.

Free Radic. Biol. Med.

Chem. Biol. Interact.

Avidity determines T-cell reactivity in abacavir hypersensitivity

Eur. J. Immunol.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents

Cytokine profiling in abacavir hypersensitivity patients

Antivir. Ther.

Abacavir and cardiovascular risk

Curr. Opin. Infect. Dis.

Oxidative bioactivation of abacavir in subcellular fractions of human antigen presenting cells

Chem. Res. Toxicol.

T-cells from HLA-B*57:01+ human subjects are activated with abacavir through two independent pathways and induce cell death by multiple mechanisms

Chem. Res. Toxicol.

Personalized medicine for HLA-associated drug-hypersensitivity reactions

Pers. Med.

The polymorphism in aldehyde dehydrogenase-2 gene is associated with elevated plasma levels of high-sensitivity C-reactive protein in the early phase of myocardial infarction

Tohoku J. Exp. Med.

Reactive aldehyde metabolites from the anti-HIV drug abacavir: amino acid adducts as possible factors in abacavir toxicity

Chem. Res. Toxicol.

N-terminal valine adduct from the anti-HIV drug abacavir in rat haemoglobin as evidence for abacavir metabolism to a reactive aldehyde in vivo

Br. J. Pharmacol.

Abacavir: absolute bioavailability, bioequivalence of three oral formulations, and effect of food

Pharmacotherapy

Abacavir and cardiovascular risk: reviewing the evidence

Curr. HIV/AIDS Rep.

1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity

Antimicrob. Agents Chemother.

Transgenic overexpression of aldehyde dehydrogenase-2 rescues chronic alcohol intake-induced myocardial hypertrophy and contractile dysfunction

Circulation

European Guidelines for Treatment of HIV Infected Adults in Europe

Distribution of alcohol and sorbitol dehydrogenases. Assessment of mRNA species in mammalian tissues

Eur. J. Biochem.

Mini review
Bioactivation to an aldehyde metabolite—Possible role in the onset of toxicity induced by the anti-HIV drug abacavir