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NRTIs
and Pathogenesis
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NRTIs
do not affect human DNA enzymes, with the exception of DNA polymerase
g |
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This
enzyme is responsible for replicating mitochondrial DNA (mt
DNA)
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NRTIs
have the potential to cause mitochondrial toxicity |
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When
inhibitory effects on DNA polymerase g and mt DNA synthesis
are present, lactic acid production increases |
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The nucleoside reverse transcriptase inhibitors (NRTIs) have been
implicated in the pathogenesis of lactic acidosis in patients with
HIV infection. This class of antiretroviral agents has a direct impact
on DNA synthesis in mitochondria, energy-producing units inside cells.1
• DNA polymerases are enzymes that catalyze the formation of
new DNA strands on a template during DNA synthesis. Among these polymerases,
DNA polymerase gamma has been found to be inhibited in vitro by NRTIs.
• This particular type of polymerase is responsible for mitochondrial
DNA replication. This replicated DNA encodes some of the mitochondrial
proteins involved in oxidative phosphorylation. The inhibitory action
of NRTIs on this enzyme can easily interfere with mitochondrial replication
and function. This results in a decreased content of mitochondrial
DNA and an increase in the number of mutations. Damaged DNA inhibits
oxidative phosphorylation and causes mitochondrial toxicity.
• In vitro studies have demonstrated that when these inhibitory
effects on polymerase gamma and mitochondrial DNA synthesis are present,
lactic acid production increases.
Reference:
1. Brinkman K, ter Hofstede HJM, Burger DM et al. Adverse effects
of reverse transcriptase inhibitors: mitochondrial toxicity as common
pathway. AIDS. 1998;12:1735-44.
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