Erythromycin as a potential precipitating agent in the onset of Leber’s hereditary optic neuropathy Corneliu C. Luca a , Byron L. Lam b , Carlos T. Moraes a,c, * a Department of Cell Biology and Anatomy, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA b Department of Ophthalmology, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA c Department of Neurology, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA Received 24 March 2004; received in revised form 12 May 2004; accepted 18 May 2004 Abstract A 23-years-old male entered a safety clinical trial for cetirizine (a selective histamine H 1 -receptor antagonist) in combination with the antibiotic erythromycin. Within a few weeks of finishing the trial, the patient reported bilateral vision loss with optic nerve atrophy. Genetic studies showed that he had a mitochondrial DNA (mtDNA) mutation at position 11778 (within the gene for subunit 4 of NADH-coenzyme Q oxidoreductase), commonly associated with Leber’s hereditary optic neuropathy. To test if erythromycin could worsen the mitochondrial respiratory chain defect associated with the 11778 mtDNA mutation, we transferred the patient’s mtDNA to cultured mtDNA-less osteosarcoma cells. Erythromycin inhibited proliferation of the patient’s transmitochondrial cybrids in conditions that required mitochondrial respiration for growth. We confirmed that erythromycin is a potent inhibitor of mitochondrial translation in these cells. Taken together, these results suggest that erythromycin may have hastened a bioenergetics crisis in the optic nerve of this patient. This association underscores the importance of being cautious with the use of drugs that interfere with cellular respiration in individuals with an underlying mitochondrial dysfunction. q 2004 Elsevier B.V. and Mitochondria Research Society. All rights reserved. Keywords: Erythromycin; Leber’s hereditary optic neuropathy; Transmitochondrial cybrids 1. Introduction Mitochondrial disorders have a variable age of onset, and this variability has been attributed to a number of factors. In the case of heteroplasmic mtDNA mutations, the percentage of mutated mitochondrial genome plays an important role in the onset and organ involvement. In the case of homoplasmic mtDNA mutations, such as in the majority of patients with Leber’s hereditary optic neuropathy (LHON), the age of onset is extremely variable (6–60 years old) and the severity and potential recovery of some vision are also unpre- dictable. This variability has been attributed to the specific mutation, genetic background as well as to environmental factors, such as alcohol and tobacco 1567-7249/$20.00 q 2004 Elsevier B.V. and Mitochondria Research Society. All rights reserved. doi:10.1016/j.mito.2004.05.002 Mitochondrion 4 (2004) 31–36 www.elsevier.com/locate/mito * Corresponding author. Address: Department of Neurology, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA. Tel.: þ 1-305-243-5858; fax: þ 1-305- 243-3914. E-mail address: cmoraes@med.miami.edu (C.T. Moraes).