Back in the stages of an early reality, Chemistry 24 or Basic Biochemistry appeared as a prerequisite at the University of California.  The majority of this introductory class focuses on enzymes, their structure, their function and their chemical properties.  Enzymes are folded polypeptides that enable chemical reactions that would not occur naturally to proceed with rapidity and finality.  Each enzyme has an active site where the molecules orient to coerce a chemical reaction and an allosteric or binding site where the majority of the chemical molecules position before the reaction takes place.  After the primary chemicals line up on the enzyme the product dissociates from the allosteric site due to a decrease in intrinsic binding to the amino acids that form the allosteric site.  New molecules then diffuse out of the milieu to take their place and the reaction repeats itself rapidly.   An enzyme can increase the rate of reaction of a chemical process almost a million fold like Carbonic Anhydrase, the fastest enzyme ever studied.  The cell has a plethora of enzymes within that catalyze basic metabolic processes and also the processes that the cell type is noted for.  A majority of the class in Introductory Biochemistry studies enzyme kinetics and the types of inhibition that affect the rate of chemical processes studied.

The basic types of enzyme inhibition are reversible and non-reversible.  Non reversible inhibitors bind covalently to the enzyme, usually its active site and cause a permanent change of conformation that abolishes the enzyme function.   An example of this type of inhibition is the nerve gas agent Sarin.   Sarin is a fluorophosphates that reacts with the serine molecule of the active site of acetylcholinesterase, rendering the enzyme completely non-functional.  Clinically this appears as a nervous system short circuit with convulsions and respiratory paralysis.  Sarin is a non-reversible agent.   On a graph of enzyme activity versus inhibitor concentration, the curve is sigmoidal and logarithmic to the negative ln function. 

Reversible agents come in many different varieties. Some reversible enzyme inhibitors resemble the substrate of the enzyme to such a degree that the inhibitor competes with the active molecule in the milieu in proportion to its concentration within the cell.   The inhibitor looks like the substrate but catalysis doesn’t take place, the inhibitor dissociates and if a natural substrate is present, it binds and the reaction proceeds.  If the competitive inhibitor is in high enough concentration, it will shut down all reactions on the enzyme in the cell.  Removal of the inhibitor renders the cell reactive and metabolism proceeds.   On an activity versus inhibitor concentration graph, this type of inhibition looks like a straight line with an x and y intercept activity proceeding from high to low. 

Another type of reversible agent binds to the allosteric site on the enzyme and by stearic interactions and hydrogen bonding occupies the majority of the enzyme site and prevents substrate from diffusing from the milieu to the enzyme due to its intense binding by non-covalent interactions.  A graph of enzyme activity versus inhibitor concentration shows another straight line schema but with a steeper negative slope and x intercept closer to zero.  This description is enzyme inhibition simplified so even a novice can understand it.  The purpose of this paper is to illustrate that the current Statin agents prescribed by the AMA are reversible agents of the latter type that bind to an enzyme by hydrogen bonding and van der walls interactions and won’t let go.  Then result is death of the cell. 

The main statin of interest is Lipitor.  Lipitor and its myriad of patent analogues bind to the allosteric site of the enzyme hydroxyl-methyl-glutamyl-coenzyme A Synthetase; or HMG-Coa synthetase for short.  Hmg-Coa becomes mevalonate which is a steroid synthesis intermediate that forms cholesterol. This is the reaction that is inhibited.  Lipitor is said to prevent the formation of cholesterol thus limiting current atherosclerotic processes in the body hence less stroke and heart attack. The problem is this: mevalonate forms estrogen and androgen the sex hormones which means you become sterile with less libido.  Mevalonate also forms 21 hydroxy keto steroids like cortisone which affect vascular tonus of the mesodermal arterioles and glucose level in the blood which means the heart can’t beat as hard or fast and the pancreas fails to produce  the hormones insulin and glucagon.  In addition mevalonate also forms aldosterone, a potent mineralocorticoid that acts on the distal renal tubule to reabsorb sodium.  The body under Lipitor administration loses sodium in a diuresis and the kidney can’t work properly.  The only benefit of Lipitor administration is the liver will produce less cholesterol and bile acids for the systemic circulation and this benefit is transitory as the poisoned liver cells will ultimately fail and cause a pan lobular hepatic necrosis also known as cirrhosis of the liver.  Inhibition of mevalonate formation affects many different cell types and myriads of reactions in the body

The body naturally gets rid of cholesterol by secreting it with bile acids into the intestinal lumen.   Because cholesterol and bile acids re-absorb in a enterohepatic circulation,  the only way to excrete cholesterol is to eat tons of roughage that contain sitiosterols or chemicals that bind bile and cholesterol and excrete the steroids into the fecal stream. Lipitor will prevent the formation of cholesterol but will also inhibit other bodily processes to the extent of morbidity and/or mortality of the host.  Enzyme inhibitors as a generality are metabolic poisons.

In nature, in man, the pharmacologic agents that function well are structural analogues or receptor blockers.  Structural analogues for natural chemicals follow stoichiometric laws, don’t accumulate and the enzyme inhibition is proportional to concentration and reversible.  Receptor blockers turn off the signals that the brain and the organs give to initiate a chemical process.  This type of fine tuning is not as drastic or catastrophic as enzyme inhibitors with high degrees on allosteric binding.  Structural analogues and receptor blockers are the agents of choice for the manipulation of metabolic processes in the image of God called man.

Enzyme inhibitors are another product of an industry that gleans billions of dollars annually from Medicare in a patent medicine with a thirty year lifespan.   If a person has the genetic haplotype of a Pima Indian or the genetic defect of hyperbetalipoproteinemia, than this drug might have some benefit but these people are a minority, Hence Lipitor is an orphan drug.   The only rational treatment for high cholesterol is to stop eating meat except for fish and consume large amounts of vegetables with roughage to soak up the cholesterol.  May mankind have the courage and the intelligence to realize the truth and act accordingly?