Table 1 Mitochondrial Toxicity of NRTIs

AZT

Skeletal muscle and heart muscle. Lactic acidosis with anaerobic metabolism in many tissues including liver.

Mitochondrial myopathy including ragged red fibers; decreased muscle mtDNA, paracrystals; phosphocreatine depletion in exercised patients. Cardiomyopathy with cardiac dilatation and failure; mitochondrial cristae dissolution. Markedly elevated serum lactate; Reye's syndrome-like findings. Hepatomegaly with fatty change (steatosis). Pediatric AIDS patients are relatively resistant.

Decreased mtDNA in vitro. Decreased mtDNA, mtRNA, mitochondrial polypeptides, and mitochondrial ultrastructural damage in vivo. Low K_i for AZTTP with mammalian DNA pol-γ. Failure of exonulcleolytic excision of terminally incorporated AZT. Mixed (competitive and noncompetitive) K_i with cardiac DNA pol-γ against various templates.

Dalakas et al, 1990

Benbrik et al, 1997

Arnaudo et al, 1991

Cherrington et al, 1995

Chattha et al, 1993

Corcuera et al, 1996

d'Amati et al, 1992

Corcuera Pindado et al, 1994

Freiman et al, 1993

Eriksson et al, 1995

Herskowitz et al, 1992

Hobbs et al, 1995

Jolliet and Widmann, 1990

Martin et al, 1994

Kohler and Lewis, 1995

Nusbaum and Joseph, 1996

Lewis, 1998

Semino-Mora et al, 1994

Lewis and Dalakas, 1995

Schroder et al, 1996

Lewis et al, 2000

Wang et al, 1996

Lipshultz et al, 2000

Oxidative stress

Sinnwell et al, 1995

de la Asuncion et al, 1998

Gerschenson et al, 2000

Szabados et al, 1999

AZT inhibits adenylate kinase: Barile et al, 1994

AZT inhibits Adenine nucleoside translocator: Barile et al, 1997

AZT inhibits NADH-cytochrome c reductase: Modica-Napolitano, 1993

AZT inhibits mitochondrial permeability transition: Elimadi et al, 1997

AZT inhibits NADH oxidase Pereira et al, 1998

AZT treatment has no effect on mitochondria Herzberg et al, 1992

DDC

Peripheral nerve

Painful peripheral neuropathy in 50—100% of patients

Inhibition of mtDNA replication in MOLT cells.

Berger et al, 1993

Mitochondrial structural changes and lipid accumulation in nerves of DDC-treated rabbits.

Dubinsky et al, 1989

Merigan et al, 1989

Anderson et al, 1992, 1994

Yarchoan et al, 1990

Chen and Cheng, 1992

Chen and Cheng, 1989

Chen et al, 1991

Cherrington et al, 1995

Eriksson et al, 1995

Feldman et al, 1992

Feldman and Anderson, 1994

Keilbaugh et al, 1993

Kukhanova et al, 1995

Martin et al, 1994

Starnes and Cheng, 1987

Tsai et al, 1994

3TC

Kinetics with HeLa DNA pol-γ

Hart et al, 1992

Martin et al, 1994

Carbovir

K_m with gapped duplex DNA

Parker et al, 1991

White et al, 1989

DDI

Peripheral nerve

Painful peripheral neuropathy in 3—22% of patients

Distorted cristae and decreased mtDNA in CEM cells

Cooley et al, 1990

Lambert et al, 1990

Cui et al, 1994

Martin et al, 1994

Medina et al, 1994

Youssef and Badr, 1992

D4T

Peripheral nerve

Painful peripheral neuropathy in 55% of patients

Distorted cristae and decreased mtDNA in CEM cells

Browne et al, 1993

Cui et al, 1997

Cohen et al, 1994

Martin et al, 1994

Medina et al, 1994

FIAU

Liver, skeletal, and cardiac muscle, peripheral nerve

Lactic acidosis; hepatic failure and steatosis; renal failure; skeletal and cardiac myopathy; peripheral neuropathy

FIAU incorporation into mtDNA in vivo and in vitro. Mitochondrial structural defects and intracellular fat accumulation in vitro and in vivo. Competitive K_i of FIAUTP, FMAUTP with DNA pol-γ (0.02 μM).

Stevenson et al, 1995

Cui et al, 1995

Klecker et al, 1994

Lewis et al, 1994a, 1996, 1997

Lewis and Tankersley, 1995

Richardson et al, 1994

Tennant et al, 1998