1.D.79. The Divalent and Trivalent Cation-transporting Monoterpenoid, Hinokitiol (Hinokitiol) Family
The hydrophobic cyclic ketol, hinokitiol, probably forms a channel capable of transporting a variety of di- and trivalent cations including Fe2+, Fe3+, Mn2+, Co2+, Ni2+ Zn2+ and Cu2+. However, under physiological conditions, iron is preferentially transported, and cellular levels of the other ions are not affected (Grillo et al. 2017). Hinokitiol is a natural monoterpenoid found in the wood of trees in the family Cupressaceae. It is a tropolone derivative and one of the thujaplicins. It has a 7 membered aromatic ring with a keto group in position 1, a hydroxyl goup at position 2, three conjugated ring double carbon-carbon bonds, and an isopropane sustituent at postion 4. It is a broad spectrum metallophore.
Cioffi et al. 2015 reported correction of iron transport defects by adding hinokitiol to yeast cells. Hinokitiol can harness ion gradients to restore iron transport into, within, and/or out of cells. The same compound promotes gut iron absorption in DMT1-deficient rats and ferroportin-deficient mice, as well as hemoglobinization in DMT1- and mitoferrin-deficient zebrafish. Thus, this compound provides a general mechanism for small molecule-mediated site- and direction-selective restoration of iron transport.