THE POSSIBLE ROLE OF PHOSPHOLIPASE-A2 IN HEPATIC-MICROSOMAL LIPID-PEROXIDATION INDUCED BY 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN IN RATS

The induction of lipid peroxidation in hepatic microsomes of rodents treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is well documented. The potential mechanisms innvolved in TCDD-induced microsomal lipid peroxidation were investigated, using selected inhibitors and free radical scavengers in vitro. Rats were treated with 40-mu-g TCDD/kg orally as a single dose. Inhibitors of phospholipase A2, including a variety of phenothiazines, dibucaine, imipramine, and verapamil, inhibited in vitro microsomal lipid peroxidation in response to TCDD administration. In addition, the lipoxygenase inhibitor quercetin, and the hydrogen peroxide scavenger aminopyrine inhibited lipid peroxidation with microsomes from TCDD-treated rats. The singlet oxygen scavenger beta-carotene, the cytochrome P-450 substrate benzphetamine, and the cyclooxygenase inhibitor indomethacin produced moderate enhancement of hepatic microsomal lipid peroxidation. The results suggest that activation of phospholipase A2 may play a critical role in the metabolic events associated with hepatotoxicity and ultimate cell death produced by TCDD. The results also support the involvement of hydrogen peroxide in TCDD-induced microsomal lipid peroxidation.