J. Liu et al., METALLOTHIONEIN PLAYS LESS OF A PROTECTIVE ROLE IN CADMIUM-METALLOTHIONEIN-INDUCED NEPHROTOXICITY THAN IN CADMIUM CHLORIDE-INDUCED HEPATOTOXICITY, The Journal of pharmacology and experimental therapeutics, 276(3), 1996, pp. 1216-1223
Metallothioneins (MTs) are low-molecular weight, cysteine-rich, metal-
binding proteins. Pretreatment of animals with Zn increases tissue MT
concentrations, and protects against Cd-induced toxicity. However, Zn
treatment produces many effects in addition to increasing MT. Therefor
e, MT-I and-II knock-out (MT-null) mice were used to determine the rol
es of MT in Cd-induced hepatotoxicity and nephrotoxicity, as well as i
n Zn-induced protection. MT-null mice were more sensitive to CdCl2 (25
mu mol/kg i.p.) hepatotoxicity, as evidenced by 25-fold increases in
serum alanine aminotransferase activity, compared to 12-fold increases
in control mice. Zn pretreatment (200 mu mol/kg s.c. x 2 days) increa
sed hepatic MT 80 fold in control mice but not in MT-null mice, and pr
evented CdCl2 hepatotoxicity in control mice only. It is concluded tha
t MT plays a critical role in Cd-induced hepatotoxicity. In contrast t
o CdCl2-induced hepatotoxicity, MT-null mice were equally susceptible
as controls to the Cd-MT (CdMT) (0.1-0.4 mg Cd/kg i.v.) nephrotoxicity
, as evidenced by similar increases in urinary protein (up to 30-fold)
and glucose excretion (up to 60-fold), as well as similar extent of p
roximal tubular necrosis. Zn increased renal MT (28-fold) in control m
ice only; however, it protected against CdMT-induced renal injury in b
oth control and MT-null mice. These findings suggest that MT plays les
s of a protective role in protecting against CdMT-induced nephrotoxici
ty than CdCl2-induced hepatotoxicity, and that Zn-induced protection a
gainst CdMT-induced nephrotoxicity does not appear to be mediated thro
ugh MT.