Intracellular disposition and metabolic effects of zidovudine, stavudine and four protease inhibitors in cultured adipocytes.
OBJECTIVE
The pathogenesis of lipodystrophy caused by the HIV protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) is unclear. We have investigated the disposition of these drugs in adipocytes and the consequent effect on adipocyte metabolism and viability.


METHODS
Laboratory study utilizing two murine cell lines, 3T3-L1 and 3T3-F442A.


METHODS
Intracellular NRTI phosphate and PI concentrations were determined by HPLC and HPLC-MS/MS, respectively. The cytotoxicity of the drugs was examined on the different adipogenic stages together with their effects on glucose uptake plus or minus insulin, and on glycerol and triglyceride levels.


RESULTS
There was rapid intracellular accumulation and phosphorylation of [3H]-zidovudine and -stavudine to their phosphate metabolites in adipocytes. The NRTIs were not cytotoxic, did not affect preadipocyte protein synthesis and did not inhibit adipogenesis or induce lipolysis. PIs accumulated in adipocytes (nelfinavir>saquinavir>ritonavir>indinavir). All PIs, except indinavir, were cytotoxic and inhibited adipogenesis, increased lipolysis and impaired preadipocyte protein synthesis. PIs inhibited glucose uptake in the rank order: indinavir>saquinavir>ritonavir>nelfinavir.


CONCLUSIONS
These data demonstrate that PIs may play a role in the insulin resistance observed in lipodystrophy by affecting glucose uptake, adipogenesis and lipolysis. NRTIs alone do not seem to have any effect on adipocyte metabolism despite undergoing phosphorylation to their triphosphorylated anabolites, although their effects in combination with PIs in perturbing adipocyte metabolism warrants further investigation.
Janneh
Omar
O
Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, UK.
Hoggard
Patrick G
PG
Tjia
John F
JF
Jones
Simon P
SP
Khoo
Saye H
SH
Maher
Bridget
B
Back
David J
DJ
Pirmohamed
Munir
M
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D018119:Stavudine / Q000378:metabolism / Q000494:pharmacology*; D015215:Zidovudine / Q000378:metabolism / Q000494:pharmacology*
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D018119:Stavudine