Chronic stavudine exposure induces hepatic mitochondrial toxicity in adult Erythrocebus patas monkeys.
OBJECTIVE
To understand the mitochondrial mechanisms underlying the lactic acidosis and hepatic steatosis seen in some HIV-1-infected individuals after long-term stavudine (d4T) exposure, we have explored mitochondrial integrity in adult monkeys (Erythrocebus patas) given a daily human equivalent dose of d4T for 78 days.


METHODS
Three Erythrocebus patas (patas) monkeys were given 3 mg d4T orally twice daily (total 6 mg d4T), or approximately 1.2 mg d4T/kg body weight per day, for 78 days and compared with 3 unexposed animals. Blood taken from controls and from treated monkeys before and after drug exposure was subjected to a complete clinical chemistry profile. Liver and skeletal muscles were examined for oxidative phosphorylation enzyme specific activities, mitochondrial deoxyribonucleic acid (mtDNA) quantity by slot blot, and mtDNA integrity by Southern blot.


RESULTS
Clinical chemistry assays demonstrated few significant differences; however, one d4T-exposed monkey had a serum lactate of 8.1 mmol/L after 78 days of oral d4T ingestion. Specific activities of oxidative phosphorylation Complexes I, II, and IV were significantly altered in both livers and skeletal muscles from the d4T-exposed animals, compared with the controls (p < or = 0.05). Significant depletion of mitochondrial DNA was observed in livers of drug-exposed monkeys, but not in skeletal muscle (p < or = 0.05). Further examination of liver DNA by Southern blot confirmed hepatic mtDNA depletion in drug exposed animals.


CONCLUSIONS
The data suggest that direct examination of the liver may be required to elucidate clinical d4T-induced hepatotoxicity related to mitochondrial damage.
Gerschenson
M
M
Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
Nguyen
V T
VT
St  Claire
M C
MC
Harbaugh
S W
SW
Harbaugh
J W
JW
Proia
L A
LA
Poirier
M C
MC
D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects*; D001774:Blood Chemical Analysis; D004272:DNA, Mitochondrial / Q000187:drug effects; D042963:Electron Transport Complex II; D004901:Erythrocebus patas; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010088:Oxidoreductases / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D018119:Stavudine / Q000009:adverse effects*; D013385:Succinate Dehydrogenase / Q000378:metabolism
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D009097:Multienzyme Complexes; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase