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Titolo:
IN-VITRO AND IN-VIVO STUDIES ON THE DEGRADATION OF METALLOTHIONEIN
Autore:
KLAASSEN CD; CHOUDHURI S; MCKIM JM; LEHMANMCKEEMAN LD; KERSHAW WC;
Indirizzi:
UNIV KANSAS,MED CTR,DEPT PHARMACOL & TOXICOL,2018 BREIDENTHAL BLDG,3901 RAINBOW BLVD KANSAS CITY KS 66160 UNIV KANSAS,MED CTR,DEPT PHARMACOL TOXICOL & THERAPEUT KANSAS CITY KS66103
Titolo Testata:
Environmental health perspectives
, volume: 102, anno: 1994, supplemento:, 3
pagine: 141 - 146
SICI:
0091-6765(1994)102:<141:IAISOT>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
RAT-LIVER; CADMIUM-METALLOTHIONEIN; ZINC-METALLOTHIONEIN; CATHEPSIN-B; LOCALIZATION; HEPATOCYTES; LYSOSOMES; THIONEIN; INVITRO; KIDNEY;
Keywords:
METALLOTHIONEIN; DEGRADATION; LYSOSOMES; CATHEPSINS; INHIBITORS; MT HALF-LIFE; INDUCERS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
27
Recensione:
Indirizzi per estratti:
Citazione:
C.D. Klaassen et al., "IN-VITRO AND IN-VIVO STUDIES ON THE DEGRADATION OF METALLOTHIONEIN", Environmental health perspectives, 102, 1994, pp. 141-146

Abstract

Degradation of metallothionein (MTI from rat liver was examined. Degradation of ape-MT by liver homogenate was greater than that by cytosol. At pH 5.5, degradation by homogenate was more than that al pH 7.2. These findings suggest that proteases that function at acidic pH are probably involved in MT degradation. Because lysosomes are the principalsubcellular organelles that contain acid proteases (cathepsins), we compared the degradation of ape-MT by lysosomes and cytsosol. Ape-MT was degraded about 400 times faster by lysosomal fraction than by cytosolic fraction. To determine the relative importance of different cathepsins, we used different inhibitors. Leupeptin, which inhibits cathepsins B and L, inhibited the degradation of ape-MT by 80%, implying that cathepsins B and/or L might be very important in the intracellular turnover of MT. Cathepsin D appeared to be the least significant, becauseape-MT degradation was reduced by about 20% by inhibiting cathepsin D. When we extended this study with purified cathepsins, we obtained the same answer, i.e., the ability of different cathepsins to degrade ape-MT was in the following order. cathepsin B >> cathepsin C > cathepsin D. While ape-MT was susceptible to degradation, ZnMT and CdMT were highly resistant to degradation. Coincubation of ZnMT or CdMT with either lysosomal extract or purified cathepsins did not result in any appreciable degradation even after 16 hr. However, longer incubations did result in some degradation, especially by purified cathepsin B. interestingly, CdMT degraded little faster than ZnMT by both lysosomal extract as well as purified cathepsin B. These data suggest that metals protect MT from rapid proteolysis. By metal-titration study, we found that at least 5 moles of Zn equivalent/mole of MT dramatically reduced the degradation, by both lysosomal fraction and purified cathepsin B. This indicates that metal release might be a prerequisite for the initiation of degradation. Release of metals is possible in the lysosomes because the intralysosomal pH is close to 5.0. Therefore, we determined the displacement of metals (Zn) as a function of pH. We found that at a pH of 4.5, nearly 70% Zn was removed, and at pH 4.0 nearly al Zn wasdisplaced from MT. We propose, therefore, that lysosomes are probablyimportant in the in vivo degradation of MT, and that metal release isa prerequisite for degradation. With the release of metals in the acidic pH of lysosomes, MT becomes more susceptible to degradation, whichis probably accomplished by the cathepsins, in particular cathepsin Band/or L. The in vivo study, however, suggests that there are other factors, too, in addition to metal composition and pH, that may have profound effect on determining the half-lives of various forms of MT, atvarious stages of development.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/11/20 alle ore 06:54:19