Human carbonyl reductase overexpression in the heart advances the development of doxorubicin-induced cardiotoxicity in transgenic mice.
Doxorubicinol (dxol) is the major metabolite formed in the hearts of cancer patients being treated with the widely used chemotherapeutic agent, doxorubicin (dox). The well-documented cardiomyopathy associated with dox treatment has been studied in vitro and ex vivo providing evidence that the C-13 hydroxy metabolite, dxol, might play a key role in the development of dox-induced cardiotoxicity. In this report, we have developed transgenic mice with heart-specific expression of human carbonyl reductase (HCBR), an enzyme that metabolizes dox to dxol. Dox was rapidly converted to dxol in the hearts of the transgenic expressers, which led to advanced development of both acute and chronic cardiotoxicity. Acute cardiotoxicity was evident by a 60% increase in serum creatine kinase activity and a 5-fold increase in cardiac damage measured by electron microscopy. Myofibril degeneration was the major damage observed in acute dox toxicity. Electrocardiograph telemetry, survival data, and electron microscopy were monitored during chronic dox-induced cardiotoxicity. HCBR expressers developed cardiotoxicity 6-7 weeks before the nonexpressers. The HCBR expressers survived for 5 weeks compared with 12 weeks for the controls. Electrocardiograph profiles and necropsies showed the cause of death to be the development of cardiomyopathies leading to congestive heart failure. Levels of dxol were four times higher in the HCBR expresser hearts than in the nonexpressers. Electron microscopy data showed swelling and major structural damage of the mitochondria in the HCBR expressers. These data demonstrate that the C-13 hydroxy metabolite of dox advances the development of dox-induced cardiotoxicity in an in vivo system and suggest that heart carbonyl reductase activity may contribute to dox-induced cardiotoxicity in humans.
Forrest
G L
GL
Department of Biology, Beckman Research Institute at the City of Hope, Duarte, CA 91010, USA.
Gonzalez
B
B
Tseng
W
W
Li
X
X
Mann
J
J
D000429:Alcohol Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000633:toxicity*; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D015716:Electrocardiography, Ambulatory; D006331:Heart Diseases / Q000139:chemically induced* / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D009928:Organ Specificity
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; D003402:Creatine Kinase; C010013:adriamycinol