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About this Article
Written by: BJ Gill
Written on: May 4th, 2004
Tags: health & medicine, lifestyle
Thumbnail by: Boutwell/University of Illinois
About the Author
BJ Gill was a sophomore chemical engineering major and history minor at the University of Southern California who had plans to attend medical school in the spring of 2004. Eventually, he hopes to specialize in plastic and reconstructive surgery. When not working, he can be found wearing a Hawaiian shirt, rocking slowly in his chair whilst listening to a mix of mid-90s pop-rock and sipping on a cool glass of iced tea.
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Volume VI Issue II > The Botox Lowdown: Science, Safety, and Success
The Botox injection is by far the most popular cosmetic procedure performed today. Botox, or Botulinum toxin A, works by blocking the release of a key chemical, acetylcholine, preventing the transmittal of signals from nerve cells to muscles. This unique effect makes it useful clinically in treating neurological and neuromuscular disorders and cosmetically in smoothing facial lines. In both applications, Botox is incredibly effective. With few exceptions, it is also remarkably safe. Given its current records of safety and efficacy, Botox is assured continued success.
Editor's Note: The contents of Illumin are strictly for informational purposes only. Illumin is not a health resource and does not provide medical advice of any sort. Illumin is not a substitute for professional medical advice, treatment, or diagnosis. Please consult your physician with regard to any medical condition you may have.

Introduction

Whether you like it or not, we live in a culture obsessed with youth and beauty. And whether they like it or not, the baby boomer generation approaches elderly status, and the proportion of the population considered old is quickly increasing [1]. These two unavoidable realizations are creating an increasing need for age-defying therapies. To meet this demand, an emerging field in the pharmaceutical industry is beginning to develop. So called "cosmecueticals", or cosmetics that change the structure or function of the body, accounted for $3.4 billion in pharmaceutical sales in 2002, with sales expected to double over the next decade [2]. One such headline-grabbing cosmecuetical is Botox® (Fig. 1).
Allergan, Inc.
Figure 1: A patient before and after applying Botox.
Botulinum toxin A, given the softer sounding name "Botox" by its manufacturer, Allergan, is an increasingly popular cosmetic agent in treating facial lines and wrinkles. According to the American Society of Plastic Surgeons, doctors performed nearly 3 million cosmetic Botox injections in 2003, making it the most frequent cosmetic procedure [3].

The Science of the Toxin

Toxins secreted by the soil bacteria Clostridium Botulinum, which causes botulism, are poisonous substances found in nature [4]. The toxins affect the body at the neuromuscular junctions called synapses. At this site, Botox prevents the release of the chemical acetylcholine [5]. Acetylcholine is of paramount importance in any muscle contraction. It is the body's premier neurotransmitter, a chemical that passes or transmits information from the terminal nerve cell to the target muscle cell across the synapse. The interactive animation below (Fig. 2) outlines the biochemical mechanism of Botox, starting with the blocking of acetylcholine.
Acetylcholine release normally occurs at neuromuscular junctions. Acetylcholine is found in the terminal nerve cells enclosed within membrane-bound sacks called vesicles. The membrane of this vesicle must fuse with the cell membrane so that the acetylcholine molecules can be released into the synapse. There are three so-called SNARE proteins involved in this key process. The three SNARE proteins work together to form a protein complex needed for membrane fusion. The protein Synaptobrevin is anchored in the membrane of the vesicle and marks the vesicle. The protein Syntaxin is anchored in the cell membrane and marks the spot on the cell membrane where fusion occurs. Finally, the protein SNAP-25 acts as a bridge between the two marker proteins and is ultimately responsible for forming the fusion complex. This complex enables the fusion of the two membranes, releasing the previously enclosed acetylcholine molecules into the synapse.
Botulinum toxin works by disrupting the normal acetylcholine release process, resulting in chemical denervation and ultimately paralysis. Generally, there are three steps involved in paralysis: binding, internalization and inhibition of acetylcholine release [5]. The toxin is composed of a light chain and a heavy chain of molecules which unite to form Botox. The heavy chain causes it to bind to a specific presynaptic neuron. Once inside the cell, the toxin is activated to then cleave apart, separating the two chains. The light chain then cleaves one of the three SNARE proteins [4]. Cleavage of any of the three necessary SNARE proteins ultimately prevents the formation of the docking complex necessary for the release of acetylcholine.
Illumin
Figure 2: Flash animation that shows how Botox works through its interaction with muscle tissue. (Flash)
The eight types of C. Botulinum produce seven distinct but closely related neurotoxins, the most common being types A, B, and E [5],[6]. While they differ in chemical structure, all of the toxins possess similar properties and have common subunit structures (i.e. light and heavy chain). The minor differences do account for differences in the specific mechanism, however, the type dictates which of the three SNARE proteins will be cleaved [4].
Without acetylcholine, a muscle will not respond to neurological signals indicating movement, effectively paralyzing the muscle as seen in Figure 1. Because of these paralytic effects, botulinum toxin is fatal in large amounts. Measuring amounts of Botox is difficult because, like many drugs and vitamins, Botox is quantized in units, and units are defined differently for each substance. For Botox, one unit (1 U) is defined as the amount of toxin required to kill half a group of lab mice. The lethal dose in humans is approximately 3500 U [5]. In more specific terms, this lethal amount corresponds to a 70-kg human injected with .09-.15 ¼ g (1 ¼ g = .000001 g), inhaling .70-.90 ¼ g, or swallowing 70 ¼ g [4].
Botox can be purchased from Allergen in 100 U vials. Injections of fewer than 100 U are typically used for most cosmetic procedures. Due to a constant cell turnover at the neuromuscular junctions of the human body, such a small dose of toxin would only disrupt muscle activity for a short time, with normal function returning after 3 months [6].