Induction of metallothionein by alpha-hederin.
alpha-Hederin (alpha-Hed) is a triterpenoid saponin that has been shown to protect against some hepatotoxicants. This study examined the protective effect of alpha-Hed against cadmium (Cd) hepatotoxicity and the mechanism of protection. alpha-Hed pretreatment (100 mumol/kg, sc) dramatically decreased Cd (3.7 mg/kg, iv) hepatotoxicity as indicated by a reduction of serum alanine aminotransferase and sorbitol dehydrogenase, as well as by histopathological examination. alpha-Hed did not produce protection by decreasing the distribution of Cd to the liver, as higher amounts of Cd were found in the liver of alpha-Hed-pretreated mice. However, there was a marked alteration in subcellular distribution of Cd in the alpha-Hed-pretreated mice, with much less Cd distributing to nuclei, mitochondria, and microsomes and more in the cytosol. The increased cytosolic Cd was found primarily bound to a low-molecular-weight protein, metallothionein (MT). alpha-Hed (10-300 mumol/kg, sc) produced a dose-dependent increase in hepatic MT with a 100-fold increase over controls 24 hr after a single injection of 100 mumol/kg, as determined by the Cd/hemoglobin assay. The hepatic MT increase produced by alpha-Hed is relatively long lasting, in that it is still eight times control values 6 days after a single administration. The induction of MT was also relatively specific for the liver, as little or no increase in MT was observed in other tissues. Furthermore, alpha-Hed increased both hepatic MT-I and MT-II levels. Northern blot analysis revealed that alpha-Hed rapidly increased MT mRNA levels. In conclusion, alpha-Hed decreases the hepatotoxicity of Cd by inducing MT, which binds Cd in the cytosol, and thus reduces the amount of Cd in the critical cellular organelles. alpha-Hed is an effective inducer of both MT-I and MT-II in liver, and this effect is associated with an increase in MT mRNA.
Liu
J
J
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417.
Choudhuri
S
S
Liu
Y
Y
Kreppel
H
H
Andrews
G K
GK
Klaassen
C D
CD
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001665:Binding Sites; D015152:Blotting, Northern; D002104:Cadmium / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D019256:Cadmium Chloride; D002712:Chlorides / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology*; D014018:Tissue Distribution
D002712:Chlorides; D012333:RNA, Messenger; D012503:Saponins; C010177:beta-hederin; D002104:Cadmium; D009828:Oleanolic Acid; D008668:Metallothionein; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; D019256:Cadmium Chloride