Session: Toxicity of Antiretroviral Therapy
Location:
Exhibit Hall
Session Date:
Monday, 9/27/99
Session Time:
3:00 pm - 4:30 pm
Preclinical Investigations into the Mechanism by Which HIV Protease Inhibitors
May Induce Metabolic Disorders
G.J. Stevens, M. Chen, R. Grecko, A. Lankford, J. Harr, C. Lee, P.W. Rose
Agouron Pharmaceuticals, Inc.: San Diego, CA
Background: Carr et al. (Lancet, (1998)351:1881) described several mechanisms by
which HIV-1 protease inhibitors (PIs) may induce metabolic changes ("lipodystrophy").
Several of these proposed mechanisms were investigated. Methods: Preclinical
investigations included: 1) The effect of cytochrome P450 3A (CYP3A) inhibition on the
isomerization of all-trans-retinoic acid to the 9-cis isomer in human liver microsomes; 2)
Comparison of the 3-dimensional crystal structure of the HIV-1 protease and the cellular
retinoic acid binding protein-1 (CRABP1); 3) Assessment of the effects of PIs on
adipocyte differentiation in 3T3 L1 cells using triglyceride accumulation and glycerol
phosphate dehydrogenase activity as markers for differentiation. Results: Under the
conditions utilized for the CYP3A assays, isomerization of all trans retinoic acid was not
inhibited by the CYP3A inhibitor, troleandomycin. Although PIs inhibit CYP3A, our
findings demonstrate that the isomerization of retinoic acid would not be affected by
inhibition of this P450 isoform. Computational comparison of the crystal structure of
CRABP1 and the HIV-1 protease demonstrated no three-dimensional similarities.
Docking of nelfinavir to the CRABP1 binding site indicated that nelfinavir can bind to the
active site, however, no hydrogen bonds are formed, suggesting little interaction between
this PI and CRABP1. Thus, inhibition of CRABP1 mediated signaling of retinoic acid is
unlikely to occur by direct binding of nelfinavir. At therapeutic concentrations, PIs
decreased adipocyte differentiation to varying degrees (saquinavir > indinavir > ritonavir
> nelfinavir = amprenavir). However, currently there is no direct evidence linking these
changes in adipocyte differentiation to "lipodystrophy". Conclusion: Preclinical
investigations demonstrate that PIs do not inhibit retinoic acid and are unlikely to alter
CRABP1 biding of 9-cis retinoic acid as has been previously proposed. While results
indicate that PIs inhibit adipocyte differentiation, the relevance of this observation is not
yet known. Therefore, other mechanisms are believed responsible for the metabolic
changes associated with body fat redistribution. |
