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Investigating the molecular mechanism of toxicity following administration of recombinant human acid sphingomyelinase
Author(s) -
LaCasse Emily R,
Finn Patrick,
Murray James,
Zhang Mindy,
Lui Dapei,
McVieWylie Alison,
Andrews Laura
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a810-d
Subject(s) - acid sphingomyelinase , toxicity , ceramide , sphingomyelin , pharmacology , recombinant dna , chemistry , biochemistry , biology , gene , apoptosis , cholesterol , organic chemistry
Acid sphingomyelinase (ASM) deficiency is an autosomal recessive disorder resulting from a deficiency of the lysosomal enzyme ASM and subsequent accumulation of sphingomyelin (SM). A mouse model of ASM deficiency was created in which accumulation of SM occurs similar to the human form of the disease. Previously, we demonstrated a dose responsive toxicity following a rapid bolus administration of recombinant human ASM (rhASM) in this mouse model. Specifically, a reduction in heart rate, mean arterial pressure and activity was observed, as well as a dose‐responsive increase in pro‐inflammatory cytokines IL‐6, IL‐1αand IL‐1β. Diminishing the substrate load in mice by administering low doses of rhASM prior to the known toxic dose prevented these toxic responses suggesting that the rate of SM degradation was related to the toxicity. To investigate the molecular mechanism of this effect, gene expression profiling of several tissues following rhASM administration was performed. The results of this analysis demonstrated an activation of stress and inflammatory gene pathways downstream of the cell signaling molecule ceramide. Since ceramide is a breakdown product of SM, these results confirmed that the mechanism of toxicity is related to the degradation of SM. Furthermore, this investigation may lead to the identification of early biomarkers of toxicity that could be monitored in the clinical setting.