Mini reviewBioactivation to an aldehyde metabolite—Possible role in the onset of toxicity induced by the anti-HIV drug abacavir
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.
References (73)
- et al.
Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans
Trends Endocrinol. Metab.
(2003) - et al.
Systemic glutathione deficiency in symptom-free HIV-seropositive individuals
Lancet
(1989) - et al.
Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity
Immunity
(2008) - et al.
Expression and localization of human alcohol and aldehyde dehydrogenase enzymes in skin
Biochem. Biophys. Res. Commun.
(1999) - et al.
Species variations in cutaneous alcohol dehydrogenases and aldehyde dehydrogenases may impact on toxicological assessments of alcohols and aldehydes
Toxicology
(2003) The abacavir hypersensitivity reaction: a review
Clin. Ther.
(2002)- et al.
Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes
Free Radic. Biol. Med.
(1991) - et al.
Monitoring abacavir bioactivation in humans: screening for an aldehyde metabolite
Toxicol. Lett.
(2013) - et al.
Acyclovir-induced nephrotoxicity: the role of the acyclovir aldehyde metabolite
Transl. Res.
(2011) - et al.
Study of the mechanisms of hydrogen peroxide and hydroxyl free radical-induced cellular injury and calcium overload in cardiac myocytes
J. Biol. Chem.
(1991)
Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro
Chem. Biol. Interact.
Signaling kinases modulated by 4-hydroxynonenal
Free Radic. Biol. Med.
HIV infection decreases intracellular nicotinamide adenine dinucleotide [NAD]
Biochem. Biophys. Res. Commun.
Distribution of ethanol-induced protein adducts in vivo: relationship to tissue injury
Free Radic. Biol. Med.
Tissue-specific mRNA expression profiles of human phase I metabolizing enzymes except for cytochrome P450 and phase II metabolizing enzymes
Drug Metab. Pharmacokinet.
Immune pathomechanism of drug hypersensitivity reactions
J. Allergy Clin. Immunol.
Roles of glucuronidation and UDP-glucuronosyltransferases in xenobiotic bioactivation reactions
Chem. Biol. Interact.
The importance of glutathione in human disease
Biomed. Pharmacother.
Role of reactive aldehyde in cardiovascular diseases
Free Radic. Biol. Med.
The metabolic activation of abacavir by human liver cytosol and expressed human alcohol dehydrogenase isozymes
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.
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