HIV-protease inhibitors alter retinoic acid synthesis.
BACKGROUND
An increasing rate of highly-active antiretroviral therapy (HAART)-associated metabolic and morphological abnormalities has been reported in HIV-infected persons. Some of them resemble retinoid-related adverse events, indicating alteration(s) of retinol metabolism or of retinoic acid-mediated signalling.


OBJECTIVE
To evaluate retinol levels in patients with or without HAART and to assess the effect of antiretroviral agents on retinal dehydrogenase (RALDH), a key enzyme involved in retinoic acid synthesis.


METHODS
Plasma retinol levels, measured in six patients receiving HAART and in five others with no antiretroviral therapy, were correlated with levels of serum retinol-binding proteins. We then studied the effects of seven antiretroviral agents on RALDH activity and gene expression in a kidney-derived cell line (LLCPK).


RESULTS
Plasma retinol levels in patients receiving HAART were decreased in comparison with those not receiving antiretroviral drugs (51 +/- 5 versus 66 +/- 11 microg/dl; P = 0.03), whereas retinol-binding protein levels were increased (68 +/- 18 versus 45 +/- 10 mg/l; P = 0.04). RALDH activity was heightened by ritonavir (24%), indinavir (17%), saquinavir (17%), zalcitabine (14%), delavirdine (12%) and nelfinavir (10%) and decreased (22%) by DMP-450. RALDH gene expression was induced only by indinavir.


CONCLUSIONS
These data indicate that certain retinoid-like adverse effects in HAART-receiving patients are not due to higher retinol levels. Enhanced RALDH activity or/and gene expression by some protease inhibitors could increase retinoic acid concentrations. Elevated retinoic acid levels might be responsible for retinoid-like or other adverse effects due to alterations in the expression of retinoic acid-responsive genes.
Toma
E
E
Department of Microbiology & Infectious Diseases, Centre hospitalier de l'Université de Montréal, Hôtel-Dieu, Montreal, Quebec, Canada.
Devost
D
D
Chow Lan
N
N
Bhat
P V
PV
D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000494:pharmacology; D023241:Antiretroviral Therapy, Highly Active; D002460:Cell Line; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D050697:Retinal Dehydrogenase; D012177:Retinol-Binding Proteins / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013552:Swine; D014212:Tretinoin / Q000378:metabolism*; D019562:Viral Load; D014801:Vitamin A / Q000097:blood*
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D018894:Reverse Transcriptase Inhibitors; D014801:Vitamin A; D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; D050697:Retinal Dehydrogenase