Zinc protoporphyrin-trimethylamine-N-oxide complex involves cholesterol oxidation causing atherosclerosis.

Metabolism of food protein by gut microbes produce trimethylamine which on oxidation by hepatic flavin-containing monooxygenases is transformed to trimethylamine-N-oxide (TMAO). TMAO has recently been implicated as a biomarker for atherosclerosis. TMAO, as (CH)N-O), is ionic and so a hydrophilic molecule that is freely available in blood plasma. For the effective interaction with lipid-soluble molecules, TMAO should be phase transferred to the lipid site. We show that the free TMAO is effectively bonded to zinc protoporphyrin IX dimethyl ester [ZnPPDME] to yield [TMAOZnPPDME] using phase transfer reaction. The zinc protoporphyrin IX, [ZnPP], in general, available in blood may form [TMAOZnPP] complex. The nature of such interaction between TMAO and [ZnPP] has been structurally shown using a model complex, [TMAOZnTPP] (TPP = tetraphenylporphyrin). These complexes readily move from the polar plasma to the non-polar (lipid) site to act as the oxo-transfer agent to oxidize cholesterol causing atherosclerosis. Chromatographic and circular dichroism (CD) studies show that either TMAO or [ZnPP] alone cannot oxidize cholesterol. Free TMAO bonded with zinc-protoporphyrin IX, [ZnPP], in blood plasma as [TMAOZnPP] is transported to the lipid site and this is the reacting species to oxidize cholesterol causing atherosclerosis.