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.

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’s 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 and the molecules which are transformed are called xenobiotics.  This war, which has occupied us and our ancestors for as long we have existed, forms the basis of the field of toxicology.

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….fatness.  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 “-C-H” bond into a “-C-OH” 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 (H2O) 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.  Its purpose is to further detoxify an otherwise reactive molecule and make it more likely to be excreted.  I won’t bore you with the chemistry.  The 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.

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.

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 – 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.

Here, I will just highlight one study that came across my desk this month. It was published in 2009 in the Proceedings of the National Academy of Sciences and came from the laboratory of David Moore. One of the enzymes involved in the phenobarbital story, CAR (the Constitutive Androgen Receptor), acts as a sensor for xenobiotics. What Moore and his colleagues found was that the activation of CAR alone was sufficient to decrease blood glucose levels. Using a variety of mouse models for diabetes they demonstrated that increased CAR activity led to decreased liver production of glucose as well as increased liver utilization of glucose and a general shift to fat utilization as well. Remember that the liver is the source of non-dietary blood glucose during times of fasting and is a major contributor to the blood glucose that confounds the attempts of diabetes patients to control their disease. Remarkably, these diabetic mice in which CAR activity has been experimentally increased show improved insulin sensitivity. What this means is that somehow the system which coordinates the ancient war against plants is integrated with the system for coordinating energy storage and release. I find this profoundly interesting. Why should this be? At present, I do not have a clue. Certainly, as Moore and company point out, this provides us with a new biochemical pathway to exploit for potential therapeutics for the treatment of type 2 diabetes. It might also provide us insight into the pathogenesis of this disease. The spoils of war…

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Robert Scheinman
Robert Scheinman
11 years ago

I’ve been reading up on miRNAs, in part because I’ve been working on siRNA therapeutics. Anyway I gather that in addition to acting as guides for the RISC, those little buggers can independently interfere with translation.  I don’t know if the mechanisms are related.

Dr. Margaret A. Morris
11 years ago

Fabulous piece– thank you! The war analogy immediately brought to mind the recent claim that plant microRNA are found circulating in blood and tissues in those pesky plat-eating humans: I have my doubts about the finding with the particular target, LDLRAP1 (why would protein levels and not mRNA levels be reduced by the miRNA? If this is a real effect, perhaps it is secondary…), but, nonetheless, the idea that plants are leaving some exogenous DNA behind adds to the burden on the filtering systems like our livers.   And, for the record, you can now be quoted as saying “[Phenobarbital]… Read more »

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