Influence of oestrogens on formation of reactive oxygen species in liver microsomes of differently aged male Wistar rats

Summary Metabolic pathways of oestrogens are the formation of catechol oestrogens (CE; 2- and 4-hydroxy-oestrogens), redox cycling of CE and free radical generation, mediated through cytochrome P450 (P450) oxidase/reductase activity. We checked the oestrogens oestradiol (E 2 ), oestradiol valerate (E 2 V) and ethinyloestradiol (EE 2 ) for formation of reactive oxygen species in vitro and ex vivo in male Wistar rats in dependence on age. In liver microsomes of 10-, 30-, 60- and 270-day-old rats the influence of E 2 , E 2 V and EE 2 (10 -7 -10 -3 M) on NADPH-Fe ++ -stimulated lipid peroxidation (LPO), H 2 O 2 generation and lucigenin (LUC) and luminol (LUM) amplified chemiluminescence (CL) was investigated. The same parameters, additionally P450 content and monooxygenase activities were measured in liver 9000 × g supernatants after subchronic administration of the oestrogens (1, 10 mg/kg b. wt. orally). The most important results are the strong inhibitory capacities of the oestrogens in vitro on LPO in the order of E 2 V 2 2 , most pronounced in 10-, 60- and 270-day-old animals. In microsomes of 30-day-old rats with the highest control LPO the antioxidative effect of the oestrogens was lower. Whereas the H 2 O 2 generation was not changed by E 2 , enhanced by E 2 V, but diminished by EE 2 in all age groups, CL LUC and CL LUM were inhibited in the order of E 2 2 V 2 . Also after subchronical treatment of the rats the antioxidative action of the oestrogens was evident, microsomal LPO was inhibited in the order of E 2 2 V 2 . All oestrogens inhibited ethylmorphine N-demethylation. But enhanced H 2 O 2 generation and increased CL LUC also indicate a formation of reactive oxygen species by these oestrogens. Obviously in vitro the antioxidative phenolic structure of the oestrogens dominates, whereas after in vivo administration the dose- and age-dependent biotransformation produces prooxidative in addition to antioxidative structures.