METABOLISM, BIOACCUMULATION, AND INCORPORATION OF DIETHANOLAMINE INTOPHOSPHOLIPIDS

Diethanolamine (DEA) is a major industrial chemical which has low acut e toxicity, but, on repeat exposure, has significant cumulative toxici ty. The present work suggests that the cumulative toxicity can be attr ibuted to the fact that, unlike most small polar molecules, DEA accumu lates to high concentrations in certain tissues following repeat expos ure. The highest concentrations of DEA were seen in liver, kidney, spl een, and brain. Investigations described here have determined that DEA is metabolized by biosynthetic routes common to ethanolamine and is c onserved, O-phosphorylated, N-methylated, and incorporated into phosph oglyceride and sphingomyelin analogues as the parent compound and as i ts N-methyl and N,N-dimethyl derivatives. This is the first report of the conjugation of a xenobiotic headgroup with a natural ceramide to f orm aberrant sphingomyelins. DEA-derived phosphoglycerides constituted the majority of aberrant phospholipid following acute administration. On repeat administration, DEA bioaccumulated to plateau levels at app roximately 8 weeks. This bioaccumulation was accompanied by an increas ing degree of methylation and accumulation of aberrant sphingo-mylenoi d lipids in tissues. Uptake and incorporation of DEA into ceramide der ivatives in human liver slices were also demonstrated in the present s tudies. It is speculated that the cumulative toxicity observed on repe at administration of DEA to rats is caused in part by increasing level s of aberrant phospholipids derived from this unnatural alkanolamine.