Effects of Diphenyl Ether Herbicides on the Heme Pathway in Cultured Liver Cells

The toxicity of diphenyl ether herbicides (DPEs) in plants has been attributed to inhibition of protoporphyrinogen (PGEN) oxidase, an enzyme in the heme biosynthetic pathway. This inhibition results in accumulation of phototoxic protoporphyrin (PROTO). To assess the potential toxicity of diphenyl ether herbicides for mammals we investigated whether these chemicals also inhibit PGEN oxidase in primary cultures of chicken and rat hepatocytes. These cultures, when treated with acifluorfen were shown to accumulate PGEN. Rat hepatocyte cultures accumulated PROTO when treated with AF or AFM. However, chicken hepatocyte cultures treated with acifluorfen accumulated uroporphyrin (URO). URO accumulation is prevented by inhibitors of cytochrome P450 and by ascorbate. These results indicate that diphenyl ethers affect two different steps of the heme synthetic pathway.