Antiestrogen

Biology

Toremifene

Peroxisome

Endocrinology

Receptor

Tamoxifen

Biochemistry

Microsome

Catalase

Carcinogen

Clofibrate

Enzyme

Internal medicine

Medicine

Chemistry

Breast cancer

Cancer

European Journal of Cancer

The antiestrogenic drug tamoxifen (TAM) is a strong liver carcinogen in the rat. As peroxisome proliferators induce liver cancer probably by an epigenetic mechanism the effect of TAM on peroxisomes, peroxisomal enzymes and peroxisome proliferator inducible CYP4AI activity was studied in the rat. Comparisons were made with the new noncarcinogenic antiestrogen, toremifene (TOR), and with clofibrate (CLO). TAM, TOR (0.10 mmol/kg) or CLO (0.10 or 1.03 mmol/kg) were administered daily to female SD-rats p.o. for 14 days. Morphometric analysis of hepatocytes was performed. Peroxisomal β-oxidation (β-OX) activity and hepatic CYP4AI-dependent lauric acid 12-hydroxylase (LAH) and catalase activities were measured. The volume density (VD) of peroxisomes increased 2.4-fold in the high-dose CLO rats. In the TAM rats the VD of peroxisomes or mitochondria increased 1.8-or 1.3-fold, respectively. In the TOR rats the VD of mitochondria increased l.4-fold. Either TAM or TOR had no effect on peroxisomal β-OX or on microsomal LAH activities. The high-dose CLO increased the β-OX rate 3.4-fold and LAH activity over 10-fold (P < 0.001). Low-dose CLO had no effect on these activities. The antiestrogens had only minor effects on catalase activity. In conclusion, the slight peroxisome proliferating effect of TAM with no concomitant increase in enzyme activities does not explain its carcinogenic action. This agrees well with the recent findings that a genotoxic product of TAM metabolism is probably involved in the cancer induction process. The antiestrogenic drug tamoxifen (TAM) is a strong liver carcinogen in the rat. As peroxisome proliferators induce liver cancer probably by an epigenetic mechanism the effect of TAM on peroxisomes, peroxisomal enzymes and peroxisome proliferator inducible CYP4AI activity was studied in the rat. Comparisons were made with the new noncarcinogenic antiestrogen, toremifene (TOR), and with clofibrate (CLO). TAM, TOR (0.10 mmol/kg) or CLO (0.10 or 1.03 mmol/kg) were administered daily to female SD-rats p.o. for 14 days. Morphometric analysis of hepatocytes was performed. Peroxisomal β-oxidation (β-OX) activity and hepatic CYP4AI-dependent lauric acid 12-hydroxylase (LAH) and catalase activities were measured. The volume density (VD) of peroxisomes increased 2.4-fold in the high-dose CLO rats. In the TAM rats the VD of peroxisomes or mitochondria increased 1.8-or 1.3-fold, respectively. In the TOR rats the VD of mitochondria increased l.4-fold. Either TAM or TOR had no effect on peroxisomal β-OX or on microsomal LAH activities. The high-dose CLO increased the β-OX rate 3.4-fold and LAH activity over 10-fold (P < 0.001). Low-dose CLO had no effect on these activities. The antiestrogens had only minor effects on catalase activity. In conclusion, the slight peroxisome proliferating effect of TAM with no concomitant increase in enzyme activities does not explain its carcinogenic action. This agrees well with the recent findings that a genotoxic product of TAM metabolism is probably involved in the cancer induction process.

72 Mechanistic studies of tamoxifen hepatocarcinogenesis: Peroxisomal proliferation