Altered clearance of human alpha 2-macroglobulin complexes following reaction with cis-dichlorodiamineplatinum(II).
Clearance studies were performed in mice using alpha 2-macroglobulin (alpha 2M), alpha 2M-trypsin complex and alpha 2M-CH3NH2 complex. All three species were incubated with cis-dichlorodiamine platinum(II) (cis-DDPt) at concentrations between 9.0 microM and 1.67 mM for 4 h and then dialyzed. The clearance rate of native alpha 2M was unchanged following incubation with cis-DDPt. alpha 2M-trypsin and alpha 2M-CH3NH2 cleared rapidly from the circulation; however, reaction with cis-DDPt significantly decreased the plasma elimination rate of both complexes. Non-denaturing gel electrophoresis and alpha 2M activity assays demonstrated relative stability following incubations with cis-DDPt which markedly altered clearance. Evidence for cis-DDPt crosslinking of alpha 2M subunits was obtained; however, whether this crosslinking is involved in altered clearance remains undetermined. Iodoacetamide treatment of alpha 2M did not duplicate the effect of cis-DDPt on alpha 2M clearance, nor did it inhibit the effect of cis-DPPt on alpha 2M clearance. Plasma elimination of alpha 2M complex was also unaltered by pretreatment of mice with intravenous free cis-DDPt.
D000818:Animals; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D007460:Iodoacetamide / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D014357:Trypsin / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism*
D000511:alpha-Macroglobulins; D014357:Trypsin; D002945:Cisplatin; D007460:Iodoacetamide