1: Toxicology 2001 Aug 13;165(1):13-25
Cyproterone acetate induces a cellular tolerance to cadmium in rat liver
epithelial cells involving reduced cadmium accumulation.
Takiguchi M, Cherrington NJ, Hartley DP, Klaassen CD, Waalkes MP.
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis,
National Cancer Institute at the National Institute of Environmental Health
Sciences, 111 Alexander Drive, P.O. Box 12233, MD F0-09, Research Triangle Park,
NC 27709, USA.
Several reports indicate that some steroids, in particular sex steroid hormones,
can modify cadmium toxicity. We recently reported that cyproterone acetate (CA),
a synthetic steroidal antiandrogen that is closely related in structure to
progesterone, affects cadmium toxicity in mice. In the present study, we
investigated the effect of CA on cadmium toxicity in a rat liver epithelial cell
line (TRL 1215) in vitro. Cells were exposed to various concentrations of CA
(0,1,10, or 50 microM) for 24 h and subsequently exposed to cadmium (0,50, or
100 microM; as CdCl2) for an additional 24 h. CA pretreatment resulted in a
clear decrease in the sensitivity to cadmium. Additional time course study
showed CA pretreatment provided protection against cadmium toxicity but only
when given for 6 or more hours prior to cadmium exposure. Cellular cadmium
accumulation was markedly reduced (60% decrease) in cells pretreated for 6 or
more hours with CA. In the presence of protein synthesis inhibitors the
protective effect of CA toward cadmium toxicity was abolished. However, in the
presence of the GSH synthesis inhibitor, L-buthionine (S,R)-sulfoximide (BSO),
the protective effect of CA toward cadmium toxicity remained. CA alone increased
metallothionein (MT) levels 2.4-fold, while cadmium (50 microM) alone resulted
in a 8.9-fold increase over control. However, cadmium-induced MT synthesis was
markedly decreased by CA pretreatment probably because of reduced cadmium
accumulation. Analysis of various metal transporters by bDNA signal
amplification assay revealed that the ZnT-1 transporter gene, which encodes for
a membrane protein associated with zinc efflux, was expressed three-fold more in
CA treated cells than control. These data show that CA pretreatment provides
protection against cadmium toxicity in vitro and indicate that this protection
is due to a decreased accumulation of cadmium rather than through activation of
MT synthesis. This decrease of cellular cadmium accumulation appears to be
related to events that require protein synthesis and may be due to activation of
the genes associated with zinc efflux.
PMID: 11551428 [PubMed - indexed for MEDLINE]
1: Biol Trace Elem Res 2001 Sep;81(3):245-54
Relationship of blood trace elements to liver damage, nutritional status, and
oxidative stress in chronic nonalcoholic liver disease.
Loguercio C, De Girolamo V, Federico A, Feng SL, Crafa E, Cataldi V, Gialanella
G, Moro R, Del Vecchio Blanco C.
Centro Interuniversitario di Ricerche su Alimenti, Nutrizione e Apparato
Digerente, Facolta di Medicina, Seconda Universita, Naples, Italy.
Trace elements are involved in chronic liver diseases because these elements may
have a direct hepatic toxicity or may be decreased as a consequence of the
impaired liver function, particularly in patients with alcoholic cirrhosis
and/or malnutrition. In this study, we determined plasma and erythrocytes trace
elements in 50 inpatients with nonalcoholic chronic liver disease (11 with
biopsy-proven chronic hepatitis, 39 with cirrhosis [16 in stage A according to
Child-Pugh criteria, 23 Child B+C]), and in a control group of 10 healthy
subjects by the proton induced x-ray emission method. The relationship between
trace element concentration and the extent of liver damage, the nutritional
status (by anthropometric evaluations), and various blood markers of oxidative
stress--reduced glutathione, total lipoperoxides and malonyldialdehyde--was
investigated. We found that cirrhotics had a significant decrease of Fe, Zn, Se,
and GSH levels in the plasma and of GSH and Se in the erythrocytes with respect
to the control and chronic hepatitis groups. GSH levels were related to the
degree of liver damage; a significant direct correlation was observed among Se,
Zn, and GSH plasma values and between GSH and Se in the erythrocytes. The trace
element decrease was, on the contrary, independent of the degree of liver
function impairment and only partially affected by the nutritional status. Data
indicate that liver cirrhosis, even if not alcohol related, induces a decrease
of Se and Zn and that, in these patients, an oxidative stress is present, as
documented by the significant correlation between Se and GSH. The plasma Br
level was higher in cirrhotics with respect to the control and chronic hepatitis
PMID: 11575681 [PubMed - in process]
1: J Indian Med Assoc 2001 Jun;99(6):311, 314-5, 318-20
Arsenic and liver disease.
Guha Mazumder DN.
Department of Medicine and Gastroenterology, Institute of Postgraduate Medical
Education and Research, Calcutta.
The hepatotoxic action of arsenic, when used as a therapeutic agent, has long
been recognised. Data on liver involvement following chronic exposure to
arsenic-contaminated water are scanty. The nature and degree of liver
involvement are reported on the basis of hospital based studies in patients who
consumed arsenic contaminated drinking water for one to 15 years. Two hundred
forty-eight patients with evidence of chronic arsenic toxicity underwent
clinical and laboratory examination including liver function tests and hepatitis
B surface antigen (HBsAg) status. Liver biopsy was done in 69 cases; in 29
patients, liver arsenic content was estimated by neutron activation analysis.
Hepatomegaly was present in 190 of 248 patients (76.6%). Non-cirrhotic portal
fibrosis was the predominant lesion (91.3%) in liver histology. The maximum
arsenic content in liver was 6 mg/kg (mean 1.46 [0.42], control value 0.16
[0.04]; p <0.001); it was undetected in 6 of 29 samples studied. The largest
number of patients with liver disease due to chronic arsenicosis from drinking
arsenic contaminated water are reported. Non-cirrhotic portal fibrosis is the
predominant lesion in this population. Hepatic fibrosis has also been
demonstrated due to long term arsenic toxicity in an animal model. Initial
biochemical evidence of hepatic membrane damage, probably due to reduction of
glutathione and antioxidant enzymes, may be seen by 6 months. Continued arsenic
feeding resulted in fatty liver with serum aminotransferases elevated at 12
months and hepatic fibrosis at 15 months.
PMID: 11678619 [PubMed - in process]
1: Dig Dis Sci 2001 Oct;46(10):2080-3
Glutathione-S-Transferase M1 null genotype in autoimmune hepatitis.
Fukagawa NK, Liang P, Li M, Ashikaga T, Reddy KR, Krawitt EL.
Department of Medicine , University of Vermont College of Medicine, Burlington
Autoimmune hepatitis is associated with genes located in the major
histocompatibility complex. The search for genes at other loci that may play a
role in disease susceptibility and/or severity is an area of active
investigation in autoimmune liver diseases. Genes for
glutathione-S-transferases, enzymes that are widely distributed and collectively
metabolize carcinogens, pollutants, drugs, and a broad spectrum of harmful,
foreign compounds have been associated with liver disease. The objective of this
study was to search for a relationship between the glutathione-S-transferase Ml
null genotype and autoimmune hepatitis using polymerase chain reaction analysis.
The findings indicate that the frequency of the null genotype is not increased
in patients with autoimmune hepatitis when compared to control subjects. These
results coupled with similar ones in primary biliary cirrhosis do not support a
role for this mutation in autoimmune liver disease.
PMID: 11680579 [PubMed - in process]