Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk.
Pharmacol Res Perspect
; 5(3): e00312, 2017 06.
Article
em En
| MEDLINE
| ID: mdl-28603631
ABSTRACT
HIV-infected patients show a markedly increased risk of delayed hypersensitivity (HS) reactions to potentiated sulfonamide antibiotics (trimethoprim/sulfamethoxazole or TMP/SMX). Some studies have suggested altered SMX biotransformation in HIV infection, but hepatic biotransformation pathways have not been evaluated directly. Systemic lupus erythematosus (SLE) is another chronic inflammatory disease with a higher incidence of sulfonamide HS, but it is unclear whether retroviral infection and SLE share risk factors for drug HS. We hypothesized that retroviral infection would lead to dysregulation of hepatic pathways of SMX biotransformation, as well as pathway alterations in common with SLE that could contribute to drug HS risk. We characterized hepatic expression profiles and enzymatic activities in an SIV-infected macaque model of retroviral infection, and found no evidence for dysregulation of sulfonamide drug biotransformation pathways. Specifically, NAT1,NAT2,CYP2C8,CYP2C9,CYB5R3,MARC1/2, and glutathione-related genes (GCLC,GCLM,GSS,GSTM1, and GSTP1) were not differentially expressed in drug naïve SIVmac239-infected male macaques compared to age-matched controls, and activities for SMX N-acetylation and SMX hydroxylamine reduction were not different. However, multiple genes that are reportedly over-expressed in SLE patients were also up-regulated in retroviral infection, to include enhanced immunoproteasomal processing and presentation of antigens as well as up-regulation of gene clusters that may be permissive to autoimmunity. These findings support the hypothesis that pathways downstream from drug biotransformation may be primarily important in drug HS risk in HIV infection.
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MEDLINE
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2017
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Article