毒理学相关资料,第五章内容参考文献33.docVIP

Top of Form Copyright ? 2001 by the American Association for the Advancement of Science Volume 293(5529)? ? ? ? ? ? ?20 July 2001? ? ? ? ? ? ?pp 442-443 Protecting Against Bad Air [Sciences Compass: Perspectives: Malaria] Luzzatto, Lucio; Notaro, Rosario The authors are at the National Institute for Cancer Research, Genova, Italy. E-mail: luzzatto@hp380.ist.unige.it Outline References Graphics Figure. The global v... It was J. B. S. Haldane who first pointed out that an infectious disease causing high mortality among children could be important in shaping human evolution by exerting selective pressure on mutant genes protecting against that infection (1). Evidence is steadily accumulating that a fatal form of malaria caused by Plasmodium falciparum (an intracellular protozoan parasite of red cells) fits Haldanes description of such an infectious disease. Named by the Romans who thought that it was caused by bad air (mala aria), malaria is believed to have exerted selective pressure on variant forms of genes expressed in red blood cells, such as glucose-6-phosphate dehydrogenase (G6PD) (2). On page 455 of this issue, Tishkoff et al. (3) use molecular analyses and mathematical modeling to estimate when two of the most common G6PD variants (A- and Med) originated in humans. The evolutionary history of G6PD is a strong reminder that this enzyme is crucial for protecting cells against oxidative stress. In contrast to all other free-living organisms, obligate anaerobic Archaea (nonbacterial prokaryotes) do not have G6PD (4). G6PD maintains a balance between reduced and oxidized glutathione, a molecule that protects against oxygen free radicals. Mouse embryonic stem cells engineered to have a defective G6PD gene are exquisitely sensitive to oxygen and give rise to embryos that die in utero (5, 6). It is puzzling why G6PD deficiency is lethal in mice but not in humans. The answer is simple: All human G6PD variants discovered so far are missense mutations or small in-frame