PubMed · 10097947
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A L Peters, R Henry, S V Edelman, B J Goldstein. 1999. Keep metformin guidelines intact.. https://doi.org/10.2337/diacare.22.3.532
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BACKGROUND: Some nucleoside analogue reverse transcriptase inhibitors (NRTI) may cause depletion of mitochondrial (mt) DNA in liver by inhibiting polymerase-gamma. mtDNA depletion may contribute to lactic acidosis, steatohepatitis and liver failure. OBJECTIVE: To evaluate the long-term mitochondrial toxicity of NRTI combinations. METHODS: The HepG2 human hepatoma cell line was cultivated in the presence of zalcitabine (ddC), didanosine (ddI), stavudine (d4T), lamivudine (3TC), zidovudine (ZDV) and efavirenz at concentrations equivalent to steady-state peak plasma levels (C ), and also in one-third and 10 times C. The NRTI were added to the medium alone or in combination. Control cells were incubated without any NRTI or with efavirenz. Cell growth, lactate production, intracellular lipid droplets, mtDNA and the mtDNA-encoded respiratory chain subunit COX II were monitored over a period of up to 30 days. RESULTS: Time- and dose-dependent mtDNA depletion was observed with ddC > ddI > d4T and mtDNA depletion preceded or coincided with a decline in COX II expression, a decrease in cell growth, increased lactate production and increased intracellular lipids. 3TC and efavirenz did not affect any measurement. ZDV increased lactate moderately and cell growth was inhibited, despite normal mtDNA and COX II levels. The negative effects on some measurements were more pronounced in the 3TC-ZDV and ddC-d4T combinations, than in the single-NRTI incubations. The combination of ddI-d4T was not more toxic than ddI alone. Mitochondrial damage by ZDV, d4T, ddI, and ddC did not reach steady-state by day 25. Using a Southern blot technique, mtDNA deletions were never observed. CONCLUSION: The data indicate additive or synergistic long-term mitochondrial toxicity in some NRTI combinations.
We hypothesized that the repetition of brief epochs of hypoxemia in elite human breath-hold divers could induce an adaptation of their metabolic responses, resulting in reduced blood acidosis and oxidative stress. Trained divers who had a 7-10 year experience in breath-hold diving, and were able to sustain apnea up to 440 sec at rest, were compared to control individuals who sustained apnea for 145 sec at the most. The subjects sustained apnea at rest (static apnea), and then, performed two 1-min dynamic forearm exercises whether they breathed (control exercise) or sustained apnea (dynamic apnea). We measured arterial blood gases, venous blood pH, and venous blood concentrations of lactic acid, thiobarbituric acid reactive substances (TBARS), and two endogenous anti-oxidants (reduced glutathione, GSH, and reduced ascorbic acid, RAA). In control subjects, the three experimental conditions elicited an increase in blood lactic acid concentration and an oxidative stress (increased TBARS, decreased GSH and RAA concentrations). In divers, the changes in lactic acid, TBARS, RAA, and GSH concentrations were markedly reduced after static and dynamic apnea, as well as after control exercise. Thus, human subjects involved in a long duration training programme of breath-hold diving have reduced post-apnea as well as post-exercise blood acidosis and oxidative stress, mimicking the responses of diving animals.
Pyruvate dehydrogenase complex (PDHC) deficiency is a major cause of congenital lactic acidemia in children. PDHC catalyzes the thiamine-dependent decarboxylation of pyruvate. Thiamine treatment was effective for some patients with PDHC deficiency. We reexamined 30 patients with congenital lactic acidemia of unknown origin who had normal PDHC activity in their cultured fibroblasts using a routine assay with a high (0.4 mM) thiamine pyrophosphate (TPP) concentration. We measured the activity of PDHC in the presence of a low (1x10(-4) mM) TPP concentration, and analyzed for mutations in the E1alpha subunit gene. Three males had low PDHC activity in the presence of 1x10(-4) mM TPP. The DNA sequence of these three patients' X-linked E1alpha subunit revealed a substitution of alanine for valine at position 71 (V71A) in exon 3, phenylalanine for cysteine at position 101 (C101F) in exon 4, and glycine for arginine at position 263 (R263G) in exon 8, respectively. Thiamine treatment was effective in these three patients. Therefore, they had a thiamine-responsive PDHC deficiency due to a point mutation in the E1alpha subunit gene. PDHC activity should be measured at a low TPP concentration to detect thiamine-responsive PDHC deficiency so that thiamine treatment can be initiated as soon as possible.