Inhibition of the 1-( o-chlorophenyl)-1-( p-chlorophenyl)-2,2,2-trichloroethane ( o,p′DDT)- and estradiol-mediated induction of rat uterine ornithine decarboxylase by prior treatment with o,p′DDT, estradiol, and tamoxifen

Abstract

This study was designed to determine whether prior administration of inducers of rat uterine ornithine decarboxylase (ODC), such as 1-( o-chlorophenyl)-1-( p-chlorophenyl)-2,2,2-trichloroethane ( o,p′DDT), estradiol-17β (E 2), or tamoxifen, inhibits the elevation of ODC by subsequently administered o,p′ DDT or estradiol-17β. o,p′ DDT (10 mg/day) was injected for 2 days to ovariectomized rats. One or two days later, when the levels of ODC returned to basal levels, o,p′ DDT (10 mg) and E 2 (0.05 μg) were administered intraperitoneally and, 6 or 5 h after these injections, uterine ODC was analyzed. The pretreatment with o,p′ DDT almost entirely blocked the induction of ODC by E 2 or o,p′ DDT. In another experiment, pretreatment with o,p′ DDT for 5 or 6 days eliminated the induction of ODC after injection of o,p′ DDT on Day 7. Similarly, the treatment of rats with the antiestrogen-tamoxifen (0.1 mg/day) for 4 days completely inhibited the subsequent elevation of ODC by either E 2 or o,p′ DDT administered on the fifth day. However, attempts to block the E 2-mediated elevation of ODC by prior treatment with E 2 yielded variable results. Two possibilities were considered to attempt to explain the mechanism of inhibition of induction of ODC by o,p′ DDT and tamoxifen: (a) induction of hepatic monooxygenase by these compounds, resulting in increased metabolism of the subsequently administered o,p′ DDT and E 2 into biologically less active components; (b) involvement of putrescine, the product of ODC action, in inhibiting ODC formation at the pretranslational level or at the post-translational level. It appears unlikely that the o,p′ DDT- and tamoxifen-mediated inhibition of ODC induction was due to an increase in hepatic biotransformation of o,p′ DDT and E 2. Pretreatment with tamoxifen or E 2 did not appear to induce the formation of hepatic microsomal cytochrome P-450, a component of the monooxygenase system. Furthermore, pretreatment with 2,2-bis-( p-chlorophenyl)-1,1-dichloroethylene (a compound with a structure similar to o,p′ DDT), which is not estrogenic but like o,p′ DDT elevates hepatic monooxygenase activity, did not inhibit E 2-or o,p′ DDT-mediated induction of uterine ODC. Concerning the possibility of putrescine inhibitory action, our observations that uterine diamine oxidase activity is negligible and that o,p′ DDT administration has no effect on this enzymatic activity suggested that elevation of ODC may result in higher levels of uterine putrescine or spermidine and spermine. The finding that the administration of putrescine to ovariectomized rats inhibited uterine ODC induction by o, p′ DDT supports the treatise that inhibition of ODC elevation after initial induction of ODC by antiestrogens and o,p′ DDT is due to putrescine- or polyamine-mediated inhibition of ODC. The possible mechanism of such product inhibition of ODC is disucssed.