Tamoxifen Alters Sub-Cellular Distribution of Lysosomal Enzymes in Carcinogen Treated Rat Liver.
J.H. Carter, P. Rees, M. Domet, M. McEvoy, and D. Warshawsky*. Wood Hudson Cancer Research Laboratory, Newport, KY, 41071, and *Dept. of Environmental Health Sciences, University of Cincinnati, Cincinnati, OH, 45267.
Abstract
Tamoxifen (TAM) is a nonsteroidal antiestrogen used to treat breast cancer.
Clinical trials are testing its efficacy for chemoprevention. Following
oral doses of TAM, high levels of the drug are found in the livers of both
women and rats. TAM is a genotoxic hepatocarcinogen in rats inducing DNA
nucleotide modifications, hepatic aneuploidy, mitotic spindle disruption
and hepatomas. It is highly lipophilic and reduces the membrane fluidity
of human breast cancer cells, possibly by partitioning in hydrophobic domains
of the cell membrane. Cytotoxicity of TAM therapy correlates with modification
of membrane structure. To investigate cytotoxic effects of TAM on the liver
and on metabolism of the breast carcinogen 7,12 dimethylbenzanthracene (DMBA),
rats were pretreated for 7 days with TAM (0.3 mg/day) then given DMBA (20
mg/rat). TAM treatment continued until animals were sacrificed 7 days later.
Hepatomegaly was found in TAM treated rats. Differential centrifugation
indicated that N-acetyl-B-galactosaminidase (NABGAL), N-acetyl-B-glucosaminidase,
acid phosphatase, B-galactosidase, and B-glucuronidase (BGLUC) were localized
primarily in the heavy (H) rather than the light (L) mitochondrial fraction
of DMBA treated rat liver with realtive specific activities (RSAs) between
7.2-3.5 in H and 3.4-1.3 in L. Conversely in TAM+DMBA treated rats RSAs
for these enzymes were between 4.3-1.9 in H and 6.2-2.5 in L. The specific
activity of BGLUC was less in DMBA treated animals receiving TAM. Compared
to untreated control rat liver, the specific activities of NABGAL, a-fucosidase,
cathepsin-D and aryl sulfatase as well as alkaline phosphatase were increased
in rats receiving DMBA with or without TAM. The data are consistent with
decreased sub-cellular membrane fusion and increased sublethal autolysis
and cytotoxicity in livers of TAM treated rats exposed to a breast carcinogen.