Differential sensitivity of mouse strains to an N-alkylated imino sugar: glycosphingolipid metabolism and acrosome formation.
This review deals with the pharmacological properties of an alkylated monosaccharide mimetic, N-butyldeoxynojirimycin (NB-DNJ). This compound is of pharmacogenetic interest because one of its biological effects in mice - impairment of spermatogenesis, leading to male infertility - depends greatly on the genetic background of the animal. In susceptible mice, administration of NB-DNJ perturbs the formation of an organelle, the acrosome, in early post-meiotic male germ cells. In all recipient mice, irrespective of reproductive phenotype, NB-DNJ has a similar biochemical effect: inhibition of the glucosylceramidase beta-glucosidase 2 and subsequent elevation of glucosylceramide, a glycosphingolipid. The questions that we now need to address are: how can glucosylceramide specifically affect early acrosome formation, and why is this contingent on genetic factors? Here we discuss relevant aspects of reproductive biology, the metabolism and cell biology of sphingolipids, and complex trait analysis; we also present a speculative model that takes our observations into account.
van der Spoel
Aarnoud C
AC
Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK. aarnoud.vanderspoel@pharm.ox.ac.uk
Mott
Richard
R
Platt
Frances M
FM
D017485:1-Deoxynojirimycin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000177:Acrosome / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D065089:Glycoside Hydrolase Inhibitors; D006028:Glycosphingolipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D015394:Molecular Structure; D010597:Pharmacogenetics; D013045:Species Specificity; D013091:Spermatogenesis / Q000187:drug effects / Q000235:genetics; D013094:Spermatozoa / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D065089:Glycoside Hydrolase Inhibitors; D006028:Glycosphingolipids; D017485:1-Deoxynojirimycin; C059896:miglustat