Quiz Question. Q. I thought that enzymes that have a high-degree of specificity are enzymes that only allow one or very few macromolecules to fit into their active site. Shouldn’t quiz question 5 state “The non-specificity of the AChE active site” rather than “The great specificity of the AChE active site” because so many different things can fit into that site?
A. The intent of the question was that you recognized from the text that the AChE site is not that specific. There are many compounds that bind there and thus there are many nerve gases and insecticides that are effective.
*** Q. After reading the section on Volume of Distribution in the Tox Tutor, as well as your answers to the questions on Volume of Distribution in the Closure Section, I am still unclear as to the significance of this measurement. I think I am having a difficult time reconciling the differences between the Closure explanation and the Tox Tutor explanations. I see that the Volume of Distribution can be used to tell you how much chemical is in the body, based on your explanation. But according to the Tox Tutor explanation, Volume of Distribution indicates distribution of the chemical in the bodily fluids. What does this really tell you about a chemical? Simply because a chemical is being transported through the body, it may not be absorbed/stored so that it could have an effect, correct? Couldn’t a chemical be distributed and then simply eliminated? Per the Tox Tutor explanation, Volume of Distribution seems more of a measure of the potential of a chemical to enter your tissues, nerves, etc because it indicates how much the substance is able to travel to places where there is a chance it could be absorbed. But it doesn’t really seem to tell you anything about how much a substance is actually absorbed into the tissues, nerves, bone, etc. Am I completely off?
A. Not off at all – you’re just trying to be too scientific with what is just a utilitarian concept. In the field of pharmaco/toxico kinetics we are really interested in the concentration of the chemical at the “target site,” and how that concentration varies with dose and time. (Another branch of science, pharmaco-dynamics will study the relation between dose and effect.) But the target could be a stretch of DNA or a receptor on the cell surface or whatever, in fact often the real target site is not known. So, kinetics will study the concentration of a chemical in a convenient body fluid, usually blood, and relate that to effect. Often, it is useful to know the relationship between the administered dose and concentration in the blood. That is where volume of distribution comes in. It relates the amount of chemical administered to the concentration measured in the blood. It is not a real volume at all. A chemical that binds to tissue or some blood protein will have a very high volume of distribution, since only a small portion of it will be measured in the blood. So will a very lipophilic chemical. Knowing that allows you to compute the real amount of the chemical in the body and its rate of elimination from amounts in the blood.
* * Q. The area under the curve, (AUC) is used as a measure of bioavailability of a particular compound. This method is applicable for therapeutic as well as toxic agents. Can you give an example of a particular disease and therapy where the AUC for two treatment groups is the same yet one group achieves the primary end point of the therapy while the other does not achieve the end point?
A. For the same drug? In theory, the effects should be proportional to the AUC. The AUC might not be proportional to the dose. Some chemicals might be rapidly eliminated until a system is saturated and then the AUC rises much more rapidly with dose. In field testing of pharmaceutical drugs, there is always a difference between treatment groups. The handling of that fact is an issue in bio-statistics.
** Q. Hydroquinone converts hemoglobin to methemoglobin by converting Iron(III) to Iron(II). This is a problem for oxygen uptake (ie. respiratory depression). It seems like A LOT of chemicals (organics anyway) cause respiratory depression and I read that it is common for hemoglobin to be converted to this methemoglobin by various chemical toxins. [Remember, that word is only for xenobiotics of plant or animal origin. You could just leave it off and your meaning would be the same. ] Is the chemical just oxidizing hemoglobin or I should say oxidizing the iron? Or is the chemical mutating the DNA that creates the hemoglobin protein that holds the iron?
A. Most organic chemicals that suppress respiratory function do so via a CNS (central nervous system) mechanism, not related to hemoglobin. Mutations take a long time, years usually to have any effect. Hemoglobin has four sites that bind oxygen, but not very tightly. It is these sites that some chemicals attach. Some, like carbon monoxide, bind tighter than oxygen.
* Q. Are the enzymes found in raw foods different than the enzymes discussed in this module? Does the body produce all the enzymes it needs for proper cell function or does it rely on supplement enzymes from food?
A. “Natural food” is a religion with some people and if that is the case with you, I don’t want to argue religion. All enzymes are complex chains of amino acids – a protein – and these must be broken down into individual amino acids, or very short chains, in order to be absorbed from the GI tract. So no enzymes you eat will have any effect on your 10 k time. They might have some effect on digestion in the GI tract (but probably not), since the acids in your stomach will destroy them.
* Q. Scientific research on Gulf War (the first one) Syndrome seems to point to a wide array of symptoms reported by Veterans as being indicative of disturbances in the Ach/AchE pathway. What I have read suggests that the underlying causes are thought to be exposure to nerve agents and adverse reactions to the administration of the drug pyridostigmine, which was given to protect against nerve agents. Would it be difficult to conduct therapy using AchE-inhibiting agents on Veterans exhibiting symptoms of disturbances in the Ach/AchE pathway? Is it possible to use this therapy to restore functions once the damage has already been done? It would seem as though if this type of therapy was successful, Veterans groups would have stronger evidence by which to assert that the symptoms of Gulf War Syndrome have a physical cause, and then gain better rights for affected Veterans in terms of treatment and compensation.
A. You are entering into a difficult area. (Before I go there I will mention that I am a veteran.) I will be blunt. If you take 1000 people at random told them that last year there was chemical X in the drinking water, 50 or so would report that they “have not been feeling well.” If you took 1000 people at random and asked them how they have been feeling the last year or so, 45 would say they “have not been feeling well.” If you asked 1000 women who have had silicon breast implants you would find 55 or so would report they “ have not been feeling well.” If you hold out the possibility of compensation, the numbers go way up, of course. The origins of “not feeling well” are completely unknown, but 5% or perhaps 10% of people who go to doctors are suffering from this “disease.” The doctors have no explanation, but sometimes call it “chronic fatigue syndrome,” or “multiple chemical sensitively,” or whatever. When you look at groups with such issues, you somehow have to subtract those that were or would have suffered from “have not been feeling well” from those whose symptoms are related to the exposure. We’ll touch on other aspects of this in the module on ‘clusters.”
I don’t know of any actual exposures to nerve gas or of any troops who took the drug. For sure taking the drugs without exposure would be acutely unhealthy, but the doses are too small to seriously harm one chronically. The effect of such drugs is quite short, since those proteins are constantly renewed. A healthy person with a small exposure to nerve gas should not have any noticeable effects in a day or so. It would be likewise with the antidote.
* Q. The EPA states that 1,2 dichloro-benzene is not classifiable as to human carcinogenicity. They claim there is no human carcinogenicity data for 1,2 dichloro-benzene. They go on to state mixed results from animal studies with respect to carcinogenicity. Finally they relate an anecdotal account of workers exposed to vapors of the compound that exhibited persistent chromosomal damage. It would seem that if they went to the trouble to develop and use some fairly elaborate animal studies they would also have available to them some reasonable in vitro human models that for example use some standardized human tissue or cell cultures. Such models are common place when assessing the safety and efficacy of drugs. Why is it that these techniques do not seem to be as common in this setting?
http://www.epa.gov/iris/subst/0408.htm
A. We’ll get to that more next week. Generally there is no “human model.” We use “animal models,” which we will also discuss at length, to guess at the effects in humans. There are many tests regarding chemicals that might cause cancer, but no definite scientific method of extrapolation those tests to actual human exposures. Many methods of extrapolation sound scientific, but are not. We’ll spend some time with those concepts.
* Q. After researching Lithium Carbonate, one of my randomly picked chemicals, I discovered it is the same lithium used to treat manic depressive disorder. It also stated that the risk of lithium toxicity is quite high. What kind of lab mice do they use to test Lithium Carbonate? Are there manic depressive mice?
A. Lithium is one of the “meds” that treat mental disorders. They would not test the efficacy of the drug in mice, only its toxicity. You can order smart and dumb rats and also anxious rats, I’m not sure about mice.
* Q. It is to my understanding that the infinity of human made toxins to enzyme active and/or allosteric sites is due to the fact that evolutionarily speaking, enzymes don’t differentiate between synthetic chemicals and natural chemicals. Has there ever been a study of the offspring in populations that have been exposed to toxins, to see if manmade chemicals have influences the enzymes structures in these individuals?
A. You are getting to “Lamarckian evolution” - the giraffes’ necks got longer by stretching. That is generally not believed today and is only of historical interest. There are only “natural” chemicals, no “supernatural chemicals” that I know of. We’ll talk about that in a later cancer module. Many sensitivities and resistances to chemicals and other disease agents are genetic and often there is wide variation in populations. A chemical could kill everyone who did not have a specific resistance and the offspring of the survivors would thus carry the resistance to future generations. Might make a good science fiction plot.