A new insight into the mechanism of dioxin toxicity: relevance of leukotrien B4 accumulation to toxcity and Yusho incident

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A reduction in hepatic leukotrien B4 (LTB4) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was studied in rats and mice. The results showed that this alteration is caused by a combination of the increased expression of 5-lipoxygenase (5-LOX), a precursor-synthesizing enzyme, and the reduced expression of leukotrien C4 synthase, a enzyme which leads the precursor to the different pathway. The aryl hydrocarbon receptor (Ahr) is suggested to play a role in 5-LOX induction. This is because 5-LOX induction occurred at fewer TCDD doses in C57BL/6J mice expressing Ahr with high affinity to TCDD than in DBA/2J mice with low affinity Ahr. LTB4 is an inflammatory factor. This mediator draws neutrophils expressing myeloperoxidase (MPO) the products of which serve in cell-killing effects. In accordance with this, TCDD increased the hepatic level of MPO.