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Journal of Lipid Research, Vol. 43, 885-894, June 2002
Copyright © 2002 by Lipid Research, Inc.

Perturbation of membrane dynamics in nerve cells as an early event during bilirubin-induced apoptosis

Cecília M. P. Rodrigues^1,*, Susana Solá^*, Rui E. Castro^*, Pedro A. Laires^*, Dora Brites^* and José J. G. Moura

^* Centro de Patogénese Molecular, Faculdade de Farmácia, University of Lisbon, 1600-083 Lisbon
Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2825-114 Monte de Caparica, Portugal

¹ To whom correspondence should be addressed. e-mail: cmprodrigues{at}ff.ul.pt

Increased levels of unconjugated bilirubin, the end product of heme catabolism, impair crucial aspects of nerve cell function. In previous studies, we demonstrated that bilirubin toxicity may be due to cell death by apoptosis. To characterize the sequence of events leading to neurotoxicity, we exposed developing rat brain astrocytes and neurons to unconjugated bilirubin and investigated whether changes in membrane dynamic properties can mediate apoptosis. Bilirubin induced a rapid, dose-dependent increase in apoptosis, which was nevertheless preceded by impaired mitochondrial metabolism. Using spin labels and electron paramagnetic resonance spectroscopy analysis of whole cell and isolated mitochondrial membranes exposed to bilirubin, we detected major membrane perturbation. By physically interacting with cell membranes, bilirubin induced an almost immediate increase in lipid polarity sensed at a superficial level. The enhanced membrane permeability coincided with an increase in lipid fluidity and protein mobility and was associated with significant oxidative injury to membrane lipids. In conclusion, apoptosis of nerve cells induced by bilirubin is mediated by its primary effect at physically perturbing the cell membrane. Bilirubin directly interacts with membranes influencing lipid polarity and fluidity, protein order, and redox status.

These data suggest that nerve cell membranes are primary targets of bilirubin toxicity.

Abbreviations: EPR, electron paramagnetic resonance; NS, nitroxyl stearate

Supplementary key words bilirubin neurotoxicity • cell death • electron paramagnetic resonance spectroscopy • membrane lipid and protein structure • oxidative stress • spin labels

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