We have fought with the enemy for as long as we can remember – millennia or perhaps eons. The war is as old as we are; older in fact. But, it does not define us. Indeed we do not think much of it. It has become a trifling thing, an autonomic thing. Nowadays, we invite the enemy into our home. We walk among them even as the war rages and we feel peace. Indeed we need them now.<\/p>\n
It was in the Ordovician period (the second of the Paleozoic era) that plants began to emerge on land. They lived unmolested for perhaps 300 million years before the first land animals emerged. It is not clear when land animals tried to eat plants but one can imagine that from the plant\u2019s point of view, this was pretty hostile behavior. Since plants are not mobile, they evolved a different strategy of protection. Those plants that were capable of generating toxic substances became poisonous to animals and thus had a selective advantage. Animals, in turn, eventually evolved rudimentary enzymes that could inactive those first toxins making those plants edible again. The war had begun. In mammals, the organ which has taken up the brunt of the job of detoxification is the liver. Other organs such as the lung and kidney do get involved but not to the same extent. We call the process biotransformation<\/em> and the molecules which are transformed are called xenobiotics<\/em>.\u00a0 This war, which has occupied us and our ancestors for as long we have existed, forms the basis of the field of toxicology.<\/p>\n It is fall now and as a member of the Toxicology program I do need to teach some toxicology on occasion. The liver handles toxicants through two major sets of reactions. Phase 1 reactions try to make the compound more soluble in water and conversely, less soluble in fat. Remember that oil and water do not mix. Fats are essentially oils that have a different melting point. Our cell membranes are little balloons of fat, studded with receptors and other proteins. Membranes within the cell such as endoplasmic reticulum are little tubes of fat that break up and reform with surprising resilience given their\u2026.fatness.\u00a0 Toxicants that are fat soluble (hydrophobic or water hating) will insert into these fatty membranes and in doing so will vastly increase their residence time. Water soluble compounds that are not useful (i.e. do not bind to something nailed down) are quickly moved into the waste stream and flushed out of the cell and eventually the body. One makes a compound more water soluble by placing a charge on it. The enzymes which do this use a variety of strategies; too many to talk about here. One example is to use oxygen. A typical situation would be to change a \u201c-C-H\u201d bond into a \u201c-C-OH\u201d bond. Because oxygen is large as compared to carbon it attracts the electrons. These electrons create a net negative charge for the molecule and the spot which is now missing those electrons has a net positive charge. Since water (H2<\/sub>O) also has this positive\/negative dipole property the transformed toxicants now prefer to associate with water and so have become soluble. Phase II reactions involve tacking on a non-reactive group to the molecule. For this reason we refer to them as conjugation reactions.\u00a0 Its purpose is to further detoxify an otherwise reactive molecule and make it more likely to be excreted.\u00a0 I won\u2019t bore you with the chemistry. \u00a0The important take-home message here is that while these processes work pretty well for the molecules within the environment (i.e. plant metabolites) they can have quite unpredictable effects on the many new molecules our society creates every year. Indeed, there are many well documented instances where biotransformation takes a somewhat benign molecule and turns it into a highly toxic substance.<\/p>\n There is some irony in the fact that the chemicals which once were used to poison us are now some of the healthiest substances on the planet. Vegetables are loaded with anti-cancer drugs and it is well accepted that those who eat lots of vegetables have decreased risk of developing virtually all types of cancer.<\/p>\n In addition to the things that we think of when we consider environmental exposure such as plastics and fertilizers, drugs also represent new molecules introduced into our bodies. Phenobarbital, one of the earliest anticonvulsant drugs (which is still in use), is a textbook model for biotransformation. It induces the activity of certain liver biotransformation enzymes thus ramping up the ability of the body to change the molecules that enter into its domain. It does something else of great interest. It lowers blood sugar levels \u2013 so much so that if one ignored the significant side effects it might be used as a treatment for diabetes. It is not because of these side effects (such as profound sedation). However, this observation has been noted by several investigators and interesting things have come of it.<\/p>\n