Metabolism, bioaccumulation, and incorporation of diethanolamine into phospholipids.
Diethanolamine (DEA) is a major industrial chemical which has low acute toxicity, but, on repeat exposure, has significant cumulative toxicity. The present work suggests that the cumulative toxicity can be attributed to the fact that, unlike most small polar molecules, DEA accumulates to high concentrations in certain tissues following repeat exposure. The highest concentrations of DEA were seen in liver, kidney, spleen, and brain. Investigations described here have determined that DEA is metabolized by biosynthetic routes common to ethanolamine and is conserved, O-phosphorylated, N-methylated, and incorporated into phosphoglyceride and sphingomyelin analogues as the parent compound and as its N-methyl and N,N-dimethyl derivatives. This is the first report of the conjugation of a xenobiotic headgroup with a natural ceramide to form aberrant sphingomyelins. DEA-derived phosphoglycerides constituted the majority of aberrant phospholipid following acute administration. On repeat administration, DEA bioaccumulated to plateau levels at approximately 8 weeks. This bioaccumulation was accompanied by an increasing degree of methylation and accumulation of aberrant sphingomylenoid lipids in tissues. Uptake and incorporation of DEA into ceramide derivatives in human liver slices were also demonstrated in the present studies. It is speculated that the cumulative toxicity observed on repeat administration of DEA to rats is caused in part by increasing levels of aberrant phospholipids derived from this unnatural alkanolamine.
Mathews
J M
JM
Center for Bioorganic Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
Garner
C E
CE
Matthews
H B
HB
D000818:Animals; D001921:Brain / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004983:Ethanolamines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008745:Methylation; D010740:Phospholipases / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D002518:Ceramides; D004983:Ethanolamines; D010743:Phospholipids; C020283:diethanolamine; D010740:Phospholipases