dinoiii
October 16th, 2006, 11:31 AM
Short Topic Series II: An Introduction to Enzymatic Targets & Phase Metabolism
Introduction
In the early nineties, the brand managers, advertising execs, and manufacturing engineers that made L’eggs panty hose were almost exclusively middle-aged men. These men decided just how high the control top should ride on a woman’s waist and divined the demand for reinforced toe. Many based their decisions upon past sales, retailer demands, and competitive offerings. Others, like Joe, occasionally wore the product to try to understand how design changes affected comfort. For all his good intentions, Joe’s natural plumbing prevented him from truly understanding the wonderful benefits of an improved cotton panel.
Dan, who worked for L’eggs ad agency, did something better. He continually sought a woman’s perspective. Dan would insist on conducting and attending user focus groups. He’d poll his wife, female co-workers, and even his mother almost daily. He made it his job to listen to people who actually wore panty hose.
Dan was a good marketer. He asked the women lots of questions. He listened very closely to their concerns, comments, and suggestions. He acted upon his knowledge. As marketers, we love to talk to ourselves. We love to talk to our colleagues, our peers, and our bosses. But many times we forget to talk to our customers.
We forget who our customers are, how they use our products, and how they relate to our companies. It’s evident in the way our communication with them is filled with industry jargon and boardroom buzzwords. We forget how to talk to them.
When we fail to make an effort to do a good job talking to our customers, do we show them that we care about them – or that we care about our business? Talking to your customers can be hard. It takes hard work to seek out your fans, ask them the right questions, and come up with the best solutions to meet their needs. Hard work indeed, but NOT talking to your customers is even harder, because when you lose touch with them, you lose their business.
Oftentimes in this industry, it is taken for granted that all of us possess the same background and the like surrounding scientific principles. We throw around various terms like aromatase and first-pass metabolism with the assumption everyone understands what this means. The reality is that some consumers may likely not and are even sometimes afraid to ask. Is it shady advertising blurred by scientific terms or our simple inability to speak at the level of the consumer? Perhaps, a degree of both.
So, I have kept you in mind with writing this piece – I have worked with the intent of catching us all up to speed and put us on the same page. This article hopes to extend beyond the science types and into a piece that those without the privy of a science degree could easily understand and in the process, hopefully be enlightened on that which you may have been afraid to ask. Maybe in the process, I have more importantly aided your understanding of a couple concepts to help you see what it is you are ingesting very readily in pill form. If so, this idea has been a success.
Enzymatic Targets
You have heard of most of them before – “aromatase,” “5 alpha-reductase,” amongst others and thanks to the pharmaceutical industry, you are likely even much more aware of the drugs that act on these targets. To make certain everyone is up to speed, it is important to understand VERY basic enzyme principles. Fortunately, it is not necessary to have ANY particular scientific background – but a working knowledge of what is happening will bode us well with this discussion in preparation for seeing how these therapies play out in practice during the next part of this series.
Enzyme is kind of a funny word to begin with. The word “enzyme” comes from the Greek breakdown:
- en = “in”
- zyme = “leaven”
These molecules (2 parts – protein + prosthetic group) are secreted by cells and act as catalysts to induce chemical changes in other substances without undergoing change themselves. The protein portion of the enzyme is called an apoenzyme that requires a prosthetic group (cofactor or coenzyme) to become a functioning enzyme.
http://i88.photobucket.com/albums/k185/dinoiii/Slide1.jpg
An important consideration of the basic figure is that the enzyme can be affected in many ways. Goals of therapeutic processes in the post-cycle era target either inhibiting formation of a metabolite or speeding up its production which may subsequently help degradation bringing things back to the homeostatic hormonal norm.
__________________________________________________
Metabolism
A related topic is one of metabolism. The act of metabolism is something that likely developed to assist humans in ridding their bodies of endogenous substances no longer needed (i.e. – catecholamines - epinephrine, norepinephrine / steroids +testosterone / bilirubin - byproduct of hemoglobin metabolism, etc…). Over time, metabolism came to include biotransformation of exogenous substances, such as food, chemicals, environmental toxins, and most importantly for our discussion – drugs (PH/PS/AAS included). Drugs are usually lipophilic (literally means – “lipid loving” or “fat loving”) which allows them to enter their site of action at target organs or tissues via cell membranes and exert their effect. Lipophilic compounds are difficult to eliminate from the body. Metabolism – or biotransformation of these compounds into more polar, inactive metabolites – is necessary. These now-water-soluble metabolites then exit the body more readily via urine, bile, or stool. The workhorses of biotransformation are the metabolic enzymes. Most of these processes occur either in the gut or in the liver; at the cellular level this takes place in something called the endoplasmic reticulum.
Now, with the evolution of C17-alkylated AAS or with many of you C17-alkylated PHs of the oral variety the term “first pass metabolism” is brought up quite frequently. This is what happens in both “passing” through the gut wall and “passing” through the liver. Most drugs actually lose functional activity during this “first pass” as the body begins the process of preparing the drug for elimination. This actually is the deciding factor that dictates how we usually administer the drug – whether via oral or intravenous. Several processes come into play contributing to what we call “first pass metabolism” which include:
- cytochrome P450 (CYP) metabolism in the gut [note: cytochrome molecules are actually enzymes; see above for basic discussion]
- complete metabolism (including additional CYP action) in the liver
Both the gut and liver also possess Phase II metabolic features as well. Instead of the cytochromes, we see fancy molecules to aid the reactions known as P-glycoproteins. In fact, the brain, kidneys, lungs, and ANY cell with endoplasmic reticulum have the capacity for some metabolic activity.
Now, it is important to understand that simply because we name them Phase I and Phase does NOT imply that all molecular metabolic processes undergo these reactions in such order. Some consist of Phase II reactions first, some consist of only Phase II, some consist of only Phase I without undergoing Phase II, and some undergo both phases at the same time.
Phase I Metabolism
The essential goal of such reactions is to add small, polar groups to parent compounds by adding or exposing a functional group on a compound or drug through various oxidative reactions. These reactions bear exotic names like: N-dealkylation, O-dealkylation, hydroxylation (which is important in the world of PH/PS/AAS), N-oxidation, S-oxidation, or deamination. The resulting compounds may in fact lose all pharmacologic activity, and they are ready for means of elimination which is the focus of Phase II reactions.
Now, we will NOT offer up blanket statements, this is simply the major pathway described above in drug elimination. Some drugs do NOT lose pharmacologic activity at all; instead their activity is enhanced. This is the prototype of the prohormone design. The metabolite actually is the molecule that imparts activity in the body.
Cytochrome P450 (CYP) Monooxidase System
As mentioned above, the most well-known of the phase I reactions (and pertinent to PH/PS/AAS talks) is the cytochrome P450 (CYP450) monooxidase system. More than 200 cytochrome enzymes exist in nature, 40 of which reside in the human body.
Six enzymes responsible for greater than 90% of the activity of this system in humans are:
- 1A2
- 3A4 (likely the most clinically significant – inclusive of PH/PS/AAS reactions)
- 2C9
- 2C19
- 2D6
- 2E1
These all sit around on a cellular organelle known as the smooth endoplasmic reticulum of both the liver cells (hepatocytes) as well as the cells of the small intestine. We reference these enzymes frequently based on their potential for drug interactions. However, our focus currently changes direction to what it means to “methylate” or “alkylate” and BYPASS FIRST PASS METABOLISM, which likely makes something orally bioactive.
First, we take an “aromatic” compound (simply defined as one that contains a ring with alternating double bonds. Understand that the circle inside of the hexane ring is simple short hand for alternating double bonds. The “R” to the top of the aromatic ring references whatever side product you choose to place there. When we talk about aromatic endocrine hormonal structures, there are 3 additional ring structures hanging off that side in place of this “R.”
When the molecule undergoes first pass metabolism – namely hydroxylation reactions, it actually tends to form an inactive byproduct. If we methylate (attach a CH3 group) this structure, does NOT have the opportunity to be transformed to the hydroxylated (-OH group attachment) product as seen in the second reaction.
http://i88.photobucket.com/albums/k185/dinoiii/Slide1-2.jpg
http://i88.photobucket.com/albums/k185/dinoiii/Slide1-1.jpg
Conclusion
Hopefully, this article made a few recurrent concepts, for those that are routinely puzzled by the “sciencey” talk, a bit more comprehendible. If so, my plight has been fulfilled. If not, my minimal hope is that it opens up the ability for those that sit back and are afraid to freely ask questions because they may be new to the game and may not want to seem like they were too far behind the rest of the crop.
Introduction
In the early nineties, the brand managers, advertising execs, and manufacturing engineers that made L’eggs panty hose were almost exclusively middle-aged men. These men decided just how high the control top should ride on a woman’s waist and divined the demand for reinforced toe. Many based their decisions upon past sales, retailer demands, and competitive offerings. Others, like Joe, occasionally wore the product to try to understand how design changes affected comfort. For all his good intentions, Joe’s natural plumbing prevented him from truly understanding the wonderful benefits of an improved cotton panel.
Dan, who worked for L’eggs ad agency, did something better. He continually sought a woman’s perspective. Dan would insist on conducting and attending user focus groups. He’d poll his wife, female co-workers, and even his mother almost daily. He made it his job to listen to people who actually wore panty hose.
Dan was a good marketer. He asked the women lots of questions. He listened very closely to their concerns, comments, and suggestions. He acted upon his knowledge. As marketers, we love to talk to ourselves. We love to talk to our colleagues, our peers, and our bosses. But many times we forget to talk to our customers.
We forget who our customers are, how they use our products, and how they relate to our companies. It’s evident in the way our communication with them is filled with industry jargon and boardroom buzzwords. We forget how to talk to them.
When we fail to make an effort to do a good job talking to our customers, do we show them that we care about them – or that we care about our business? Talking to your customers can be hard. It takes hard work to seek out your fans, ask them the right questions, and come up with the best solutions to meet their needs. Hard work indeed, but NOT talking to your customers is even harder, because when you lose touch with them, you lose their business.
Oftentimes in this industry, it is taken for granted that all of us possess the same background and the like surrounding scientific principles. We throw around various terms like aromatase and first-pass metabolism with the assumption everyone understands what this means. The reality is that some consumers may likely not and are even sometimes afraid to ask. Is it shady advertising blurred by scientific terms or our simple inability to speak at the level of the consumer? Perhaps, a degree of both.
So, I have kept you in mind with writing this piece – I have worked with the intent of catching us all up to speed and put us on the same page. This article hopes to extend beyond the science types and into a piece that those without the privy of a science degree could easily understand and in the process, hopefully be enlightened on that which you may have been afraid to ask. Maybe in the process, I have more importantly aided your understanding of a couple concepts to help you see what it is you are ingesting very readily in pill form. If so, this idea has been a success.
Enzymatic Targets
You have heard of most of them before – “aromatase,” “5 alpha-reductase,” amongst others and thanks to the pharmaceutical industry, you are likely even much more aware of the drugs that act on these targets. To make certain everyone is up to speed, it is important to understand VERY basic enzyme principles. Fortunately, it is not necessary to have ANY particular scientific background – but a working knowledge of what is happening will bode us well with this discussion in preparation for seeing how these therapies play out in practice during the next part of this series.
Enzyme is kind of a funny word to begin with. The word “enzyme” comes from the Greek breakdown:
- en = “in”
- zyme = “leaven”
These molecules (2 parts – protein + prosthetic group) are secreted by cells and act as catalysts to induce chemical changes in other substances without undergoing change themselves. The protein portion of the enzyme is called an apoenzyme that requires a prosthetic group (cofactor or coenzyme) to become a functioning enzyme.
http://i88.photobucket.com/albums/k185/dinoiii/Slide1.jpg
An important consideration of the basic figure is that the enzyme can be affected in many ways. Goals of therapeutic processes in the post-cycle era target either inhibiting formation of a metabolite or speeding up its production which may subsequently help degradation bringing things back to the homeostatic hormonal norm.
__________________________________________________
Metabolism
A related topic is one of metabolism. The act of metabolism is something that likely developed to assist humans in ridding their bodies of endogenous substances no longer needed (i.e. – catecholamines - epinephrine, norepinephrine / steroids +testosterone / bilirubin - byproduct of hemoglobin metabolism, etc…). Over time, metabolism came to include biotransformation of exogenous substances, such as food, chemicals, environmental toxins, and most importantly for our discussion – drugs (PH/PS/AAS included). Drugs are usually lipophilic (literally means – “lipid loving” or “fat loving”) which allows them to enter their site of action at target organs or tissues via cell membranes and exert their effect. Lipophilic compounds are difficult to eliminate from the body. Metabolism – or biotransformation of these compounds into more polar, inactive metabolites – is necessary. These now-water-soluble metabolites then exit the body more readily via urine, bile, or stool. The workhorses of biotransformation are the metabolic enzymes. Most of these processes occur either in the gut or in the liver; at the cellular level this takes place in something called the endoplasmic reticulum.
Now, with the evolution of C17-alkylated AAS or with many of you C17-alkylated PHs of the oral variety the term “first pass metabolism” is brought up quite frequently. This is what happens in both “passing” through the gut wall and “passing” through the liver. Most drugs actually lose functional activity during this “first pass” as the body begins the process of preparing the drug for elimination. This actually is the deciding factor that dictates how we usually administer the drug – whether via oral or intravenous. Several processes come into play contributing to what we call “first pass metabolism” which include:
- cytochrome P450 (CYP) metabolism in the gut [note: cytochrome molecules are actually enzymes; see above for basic discussion]
- complete metabolism (including additional CYP action) in the liver
Both the gut and liver also possess Phase II metabolic features as well. Instead of the cytochromes, we see fancy molecules to aid the reactions known as P-glycoproteins. In fact, the brain, kidneys, lungs, and ANY cell with endoplasmic reticulum have the capacity for some metabolic activity.
Now, it is important to understand that simply because we name them Phase I and Phase does NOT imply that all molecular metabolic processes undergo these reactions in such order. Some consist of Phase II reactions first, some consist of only Phase II, some consist of only Phase I without undergoing Phase II, and some undergo both phases at the same time.
Phase I Metabolism
The essential goal of such reactions is to add small, polar groups to parent compounds by adding or exposing a functional group on a compound or drug through various oxidative reactions. These reactions bear exotic names like: N-dealkylation, O-dealkylation, hydroxylation (which is important in the world of PH/PS/AAS), N-oxidation, S-oxidation, or deamination. The resulting compounds may in fact lose all pharmacologic activity, and they are ready for means of elimination which is the focus of Phase II reactions.
Now, we will NOT offer up blanket statements, this is simply the major pathway described above in drug elimination. Some drugs do NOT lose pharmacologic activity at all; instead their activity is enhanced. This is the prototype of the prohormone design. The metabolite actually is the molecule that imparts activity in the body.
Cytochrome P450 (CYP) Monooxidase System
As mentioned above, the most well-known of the phase I reactions (and pertinent to PH/PS/AAS talks) is the cytochrome P450 (CYP450) monooxidase system. More than 200 cytochrome enzymes exist in nature, 40 of which reside in the human body.
Six enzymes responsible for greater than 90% of the activity of this system in humans are:
- 1A2
- 3A4 (likely the most clinically significant – inclusive of PH/PS/AAS reactions)
- 2C9
- 2C19
- 2D6
- 2E1
These all sit around on a cellular organelle known as the smooth endoplasmic reticulum of both the liver cells (hepatocytes) as well as the cells of the small intestine. We reference these enzymes frequently based on their potential for drug interactions. However, our focus currently changes direction to what it means to “methylate” or “alkylate” and BYPASS FIRST PASS METABOLISM, which likely makes something orally bioactive.
First, we take an “aromatic” compound (simply defined as one that contains a ring with alternating double bonds. Understand that the circle inside of the hexane ring is simple short hand for alternating double bonds. The “R” to the top of the aromatic ring references whatever side product you choose to place there. When we talk about aromatic endocrine hormonal structures, there are 3 additional ring structures hanging off that side in place of this “R.”
When the molecule undergoes first pass metabolism – namely hydroxylation reactions, it actually tends to form an inactive byproduct. If we methylate (attach a CH3 group) this structure, does NOT have the opportunity to be transformed to the hydroxylated (-OH group attachment) product as seen in the second reaction.
http://i88.photobucket.com/albums/k185/dinoiii/Slide1-2.jpg
http://i88.photobucket.com/albums/k185/dinoiii/Slide1-1.jpg
Conclusion
Hopefully, this article made a few recurrent concepts, for those that are routinely puzzled by the “sciencey” talk, a bit more comprehendible. If so, my plight has been fulfilled. If not, my minimal hope is that it opens up the ability for those that sit back and are afraid to freely ask questions because they may be new to the game and may not want to seem like they were too far behind the rest of the crop.