Molecular effects and retinopathy induced by hydroxychloroquine during SARS-CoV-2 therapy: Role of CYP450 isoforms and epigenetic modulations

Abstract

Antimalaria drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) have been administered to several inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus, and infectious diseases such as acquired immune deficiency syndrome and influenza. Recently, several patients infected with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were given HCQ, and showed a discrepant response. HCQ inhibits SARS-CoV-2 cell entry, and inflammatory cascade by interfering with lysosomal and endosomal activities, and autophagy, impeding virus-membrane fusion, and inhibiting cytokine production resulted from inflammatory pathways activation. Despite ongoing administration of HCQ in a wide spectrum of disorders, there are some reports about several side effects, especially retinopathy in some patients treated with HCQ. Cytochrome P450 (CYP450) and its isoforms are the main metabolizers of HCQ and CQ. Pharmacokinetic properties of CYP enzymes are influenced by CYP polymorphism, non-coding RNAs, and epigenetic mechanisms such as DNA methylation, and histone acetylation. Accumulating evidence about side effects of HCQ in some patients raise the possibility that different response of patients to HCQ might be due to difference in their genome. Therefore, CYP450 genotyping especially for CYP2D6 might be helpful to refine HCQ dosage. Also, regular control of retina should be considered for patients under HCQ treatment. The major focus of the present review is to discuss about the pharmacokinetic and pharmacodynamic properties of CQ and HCQ that may be influenced by epigenetic mechanisms, and consequently cause several side effects especially retinopathy during SARS-CoV-2 therapy.

Disease-drug and drug-drug interaction in COVID-19: Risk and assessment

“…Both change into active metabolites through the dealkylation process by CYP isomers [138] , [139] . The single nucleotide polymorphism (SNPs) of CYP2D6 showed on the variable metabolism of HCQ and CQ in SLE [140] . The administration of HCQ for the management of COVID-19 infection was challenged by several side effects among individuals with different CYP genotypes.…”

The epigenetic implication in coronavirus infection and therapy

“…Clinical trials, FDA approved epigenetic-targeted agents, and combination therapy of epigenetic and antiviral drugs is currently considered as useful and beneficial for viral replication impairment and the control of the host immune response [ 83 ]. Remarkably, pharmacokinetic and pharmacodynamic properties of antivirals may also be influenced by epigenetic regulation, highlighting, once again, their relevance in the treatment SARS-CoV-2 infection [ 84 ]. Recently, El Baba and coworkers analyzed several epigenetic mechanisms involved in coronaviruses infections, identifying some major epigenetic player which can be therapeutically targeted [ 83 ].…”

Novos sistemas de delivery, uso tecnológico e reposicionamento da cloroquina e hidroxicloroquina: Uma revisão integrativa

“…A atividade anti-inflamatória da Research, Society and Development, v. 10, n. 7, e29910716589, 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10. 33448/rsd-v10i7.16589 3 HCQ pode também estar relacionada com uma possível interferência na via de sinalização dos receptores do tipo Toll no componente inato do sistema imune (dos Reis Neto et al, 2020;Paniri et al, 2020).…”