High cholesterol and excess free radicals in the body are major risk factors for developing cardiovascular diseases (CVD). Healthy lifestyle and low cholesterol intake certainly help prevent CVD, but people still often fail to maintain the levels of cholesterol required.
Most cholesterol in the body does not come from food, but is produced internally. Statins reduce cholesterol levels by acting as competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, an enzyme that catalyses cholesterol biosynthesis. Yet, some people do not respond to statins.
Now, Adi Haber, Zeev Gross and colleagues at Technion – Israel Institute of Technology in Haifa, have proposed a new alternative to statins. Combining pure chemistry, biochemistry and animal studies they found that the catalytic antioxidant, 1-Fe, an iron(III) complex of an amphipolar corrole, and its analogues, inhibit HMG-CoA reductase in a way quite different to statins. ‘These compounds have nothing to do with statins,’ says Gross, ‘they are completely different entities.’
The macrocycle in 1-Fe is important for binding to HMG-CoA reductase at points where the body’s chemicals do not usually bind to inhibit the catalytic activity of the enzyme. ‘We have found a new mode of action – corroles and statins inhibit the same enzyme, but use a different mechanism,’ adds Gross.
‘Our antioxidant eliminates free radicals in a catalytic fashion,’ explains Gross, ‘antioxidants from food, wine and vitamins fight free radicals in a one-to-one reaction, where one molecule eliminates one radical. Catalytic antioxidants can take care of thousands of radicals.’
Bato Korac, who studies redox regulation mechanisms in health and disease at the University of Belgrade in Serbia, recognises the advantages of the new complex. ‘This antioxidant affects the metabolism and controls cholesterol homeostasis at multiple points – lower cellular uptake, better removal, and decreased de novo synthesis of cholesterol. These results reveal a new perspective in the treatment of hypercholesterolemic disease.’
Gross and his group now plan to study 1-Fe efficacy in other cholesterol-related diseases like diabetes.