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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5515_Библиотеки_им_академика_М_И_Перельмана.pdf
Figure 8.6. Diagram of the skin. The relevant receptor molecules and cell types are shown in the diagram.
The subcutaneous layer is below the dermis.
The dermis comes next, where hair follicles, sweat glands, and nerve endings
reside. Our CBD molecule has many potential destinations in this area of the skin too,
as all the major receptors for it are floating around this layer. The dermal layer also is
home to several kinds of touch sensory cells such as Merkel cells, and Pacinian and
Meissner’s corpuscles. The subcutaneous layer, the last layer of the skin, contains fatty
tissue for insulation and acts like padding when mechanically disturbed. The fat in this
layer is also a source for energy.
This skin structure is a lot for our CBD molecule to deal with. But what might be
the destiny of our CBD molecule when introduced to the skin via topical application?
The molecule hits the skin in the form of a topical oil or spray and is rubbed in. When it
hits the stratum corneum, it has two routes it can take to get by that brick-and-mortar
barrier. (If it doesn’t, it will remain on the surface and more than likely degrade or dry
away, prematurely ending its journey.) The two routes are transepidermal (through the
cells of the epidermis) and transappendageal (through the interstitial areas between the
epidermal cells). One can think of this latter route as finding an area of the epidermis
that needs tuckpointing; the CBD molecule will sneak through before the cell can
tuckpoint the damage. The transappendageal route simply refers to the microscopic
appendages that are embedded in the epidermis and dermis such as follicles, sweat
glands, and sebaceous glands. These appendages sometimes aren’t perfectly embedded
and leave small openings for CBD molecules to get through. Both of these routes pose
challenges. But it turns out that oil and water can soften up the skin’s layers, so our CBD
molecule gets through the stratum corneum and traverses the rest of the epidermis
without a problem.
Our CBD molecule is now in the skin’s dermis, where hair follicles, sebaceous and
sweat glands, and nerve endings reside. These all provide potential breakthrough points
with which our CBD molecule can penetrate farther into the tissue it was intended for.
There are also plenty of receptors for a CBD molecule to interact with in this region of
the skin. How CBD and THC find and interact with these receptors is another set of
stories related in chapters 10 and 11.
9
A Plant of (More Than) 1,001 Chemicals
The cannabis plant generates a huge range of chemicals that it synthesizes. Cannabis is
so effective at making these chemicals that it is called “the plant of 1,001 chemicals.”
Actually, a more accurate estimate of the number of chemicals that cannabis produces is
greater than 1,600. They are technically called phytochemicals. There is a long history
of studying them; many of the molecules that reside in plants are there for good reasons.
Two of the most common reasons are for defense (if the plant tastes bad, it won’t be
eaten) and to attract pollinators and dispersers (if the plant is attractive to animals that
move around a lot, it will be fertilized and dispersed). In an evolutionary context, some
of the phytochemicals that plants produce are successful at first, but the defensive ones
are often in an arms race with the animals that eat them. The race starts with the plant
producing a defensive molecule that an insect or larger animal finds noxious or even
lethal. Insects will at first stay away from the plant’s defensive chemical barrage, but
through evolutionary time, mutations in the genomes of the animals that the plant is
warding off can occur that will boost resistance to the noxious molecule. The animals
can now take advantage of the plant without getting sick or dying.
The cycle will start over again when the plant escalates the arms race by evolving
a more efficient version of the first molecule or even a brand-new noxious chemical.
The vast number of plant secondary compounds that exist as defensive chemicals is
good evidence of the lack of truces or even détentes in this arms race. In many cases a
race is evident from understanding how animals develop resistance. Because a lot of
these evolutionary cycles involve insulting the taste buds of other organisms, many plant
phytochemicals are bitter, oily, tough to digest, or downright toxic to the animals eating
the plant. And many of these defense and attraction phytochemicals have been used by
humans for a wide range of other purposes.
Of the 1,001 chemicals, the major categories that are involved in marijuana
potency, taste, smell, texture, and overall pleasantness are flavonoids, lignins,
sesquiterpenes, triterpenes, monoterpenes, and cannabinoids. Cannabinoids are of
course where the action is when it comes to medicinal and recreational purposes, but
the other phytochemicals may turn out to be equally important.
Flavonoids
Each of the six types of chemicals I consider have distinctively shaped molecules that
are important to their function. They have a basic skeleton consisting of atoms from the
six basic building blocks of animal life: CHNOPS, or carbon, hydrogen, nitrogen,
oxygen, phosphate, and sulfur. Often the carbon atoms form many-sided rings that are
drawn as hexagon-like figures in chemical diagrams. These hook together to flesh out
the basic skeleton of a group of related chemicals such as the flavonoids. Flavonoids
have three of these rings in their basic skeletal structure. A flavonoid looks like a small
puppy: neck, ears, and head, with two of the rings making up its body and one its head.
Luteolin (fig. 9.1) offers a good example; its ears and tail are clearly positioned.
What makes one flavonoid different from the next is based on differences inherent
in each “puppy.” If the puppy has two ears (those hydroxyl or OH structures coming off
the head of the skeleton in luteolin in figure 9.1), then it can be any one of several
flavonoids. Puppies with two ears can either be lying down or standing up. Standing
puppies can have their heads up or can be “eating” with their heads down. The upright
puppy can either be standing still or jumping. All of these different puppies occur when
there are very slight changes to the basic skeleton, such as adding or subtracting an OH
group. In all, there are over 5,000 puppies that have been characterized as flavonoids
from nature.
Figure 9.1. Flavonoid “puppies.” Morphing from one puppy to the next can be accomplished with simple
chemical changes. For instance, the basic puppy can change into a one-eared puppy by losing one of the
OH groups on its head. The “sleeping puppy” is shown on its back.
Just as there are breeds of dogs, there are also major basic categories of
flavonoids. There are five major ones: flavones, flavonols, isoflavones, anthocyanins,
and chalcones. Each is characterized by having a distinctive basic skeleton that has
slight alterations to it, as described previously for the puppies.
Flavonoids are found in a broad array of plants—both fruits and vegetables. They
are thought to be associated with broad-spectrum health-promoting effects and are
included in a wide range of medicinal products. The wide-ranging medicinal
characteristics of flavonoids reside in their chemical nature and shapes—those ringlike
structures that make up the puppies’ bodies. Those ring structures (called polyphenolic
structures) render the molecules antioxidative, anti-inflammatory, and anticarcinogenic.
Flavonoids are also important players in two of the plant kingdom’s most showy
characteristics—aroma and flower color. In cannabis the flavonoids are found in all
parts of the plant and are probably an important aspect of its overall aroma and taste.
Terpenes
Terpenes are another group of natural plant products. Perhaps the most famous terpenes
are natural rubber and paclitaxel (Taxol), an anticancer agent. All terpenes have a
similar chemical equation with five carbons and eight hydrogens repeated n times over
and over [(C5H8)n, where n can be any integer and refers to the number of times the
C5H8 can be repeated]. When n is two, making a molecule that is C10H16, the terpene is
called a monoterpene. When n is four, making a molecule that is C20H32, the terpene is
called a diterpene. When n is six it makes a molecule that is C30H48, which is called a
triterpene. Most terpenes have even-numbered n’s, except for when n is three and
makes a molecule C15H24 called a sesquiterpene (sesqui = 1.5). The number and
positions of the carbons and hydrogens dictates the characteristics of the terpene, with
over 30,000 of these kinds of molecules found in nature.
Figure 9.2. “Bar dart” monoterpenes.
Monoterpenes mostly resemble bar darts with fat barrels; some that are relevant to
our understanding of cannabis are illustrated in figure 9.2. Even those that don’t look
like darts (such as pinenes) still have a dart-like tip. Myrcene, limonene, and pinene are
all monoterpenes that influence the taste and aroma of cannabis. They are also important
because the way they are generated in plant tissues is through two biosynthetic
pathways: the MEP (methylerythritol-4-phosphate, a precursor molecule for the
pathway) and the MVA (mevalonate, another precursor molecule for this second
pathway) pathways. Some of the proteins that the plant genome makes are important
enzymes in these biosynthetic pathways, which are also significant for the synthesis of
the cannabinoids. One category of enzymes for which plant genomes code are the
monoterpene synthases. These take the preliminary chemical structures and transform
them to the terpenes, which give the plant its texture and aromatic and gustatory
characteristics. The monoterpene synthases result in important compounds such as
geraniol, myrcene, and limonene.
The triterpenes (C30H48) look a lot like five-segmented centipedes. These
molecules have a basic segmented chemical skeleton with side groups on one end that
resemble antennae (fig. 9.3). As with the flavonoids, modifying the basic structure of
these centipede skeletons with slight changes will yield different kinds of triterpenes.
Why are we so interested in the shape of these chemicals? The shape of a molecule
has everything to do with its odor, taste, and other recreational or medicinal properties.
So subtle differences in some of these molecules will often change the landscape of
how these chemicals influence our bodies. For instance, all monoterpenes have the
same chemical formula—C10H16; they are isomers of each other, which means they all
have the same number of carbons and hydrogens. If you examine the structure of these
terpenes closely, although you will see some similarities in their three-dimensional
structure, you will also observe that they differ from one another. It is these differences
that enable our taste and olfactory senses to tell many of them apart.
Figure 9.3. Centipede-like triterpenes. Four basic kinds of triterpenes are pictured, with their basic skeletons
illustrating the chemical equation C30H48.
Figure 9.4. Some stop-sign sesquiterpenes inhaled in a hit of marijuana. All the terpenes here share the
chemical formula C15H24. Despite having the same chemical formula, they all have different three-
dimensional structures.
Other terpenes cannabis produces that have drawn attention are beta-caryophyllene
(E-BCP) and humulene (fig. 9.4). No doubt about it, that skeleton is a stop sign. These
kinds of terpenes are sesquiterpenes with the chemical formula C15H24. E-BCP has
recently been reported to bind to cannabinoid receptors, suggesting that it is not only a
terpene but also could be considered a cannabinoid. E-BCP is recognized by our taste
buds as peppery. But alpha humulene triggers a hoppy taste. The slight difference in the
structures of the two molecules makes all the difference to our taste and olfactory
receptors.
Lignins
This category of major plant secondary compounds is the most complex. There is no
single lignin skeleton for the basic structure of this category of molecules, and they are
cobbled-together structures that are physically quite rigid. Their rigidity renders them
suited for structural purposes in plants. Lignins resemble subway maps, with the various
side chains of the different molecules being the red, blue, or green lines of a subway
system (fig. 9.5). The carbon rings in lignin function as the “stations” in the system, and
the bonds are the “tracks.” Just as Tokyo’s subway system is different from the Paris
Métro, which is equally different from the MTA in New York City, so are the lignin
molecules that give structure and rigidity to plant tissues, mostly by shoring up the cell
membranes of plant tissues. Although the primary utility of lignin in plants is structural,
these molecules can also be involved in texture, odors, and taste.
The beauty of these phytochemicals lies not in their simplicity of structure (they can
be quite complex structurally, as the lignins demonstrate), but rather in the simplicity
with which they are generated and the simplicity with which a large degree of novel
molecules can be created with only slight changes in side chains and specific parts of
the chemical skeleton.
Cannabinoids
There are two major synthetic endpoints for this category of secondary compounds:
THCA and CBDA, which are the stars of this book. These two chemicals were
discussed in some detail in chapter 7 when we addressed decarboxylation—that
magical chemical step that converts THC and CBD acid precursors into their
decarboxylated potent forms. But there I black-boxed most of the molecule (see fig. 7.1)
and exposed only the parts of the THCA and CBDA molecules that are the targets of
decarboxylation. Let’s take a closer look at what is behind those black boxes.
Other plants like those in the genus Echinacea also produce cannabinoids, but it is
cannabis where the real deals (THCA and CBDA) are found. There are over 100
cannabinoids that have been isolated so far from cannabis. They mostly share the
chemical equation C21H30O2. There are ten major cannabinoids in marijuana (fig. 9.6).
When I examine the cannabinoid structures that these molecules take, I see the baby
alien that popped out of John Hurt’s torso in the first Alien movie. The creature is
complete with a tail, legs for scurrying around, and a bizarre head only a mother could
love. The two major cannabinoid endpoints (CBD and THC) are accompanied by a
wide range of other cannabinoids that are only now being examined for their impact
when ingested. Table 9.1 lists some of the various cannabinoid type classes that have
been discovered so far. Of the 480 or so compounds already characterized, 180 can be
categorized as cannabinoids, of which 120 are listed in table 9.1. Of these, about 150
are also classified as terpenes.
Figure 9.5. Lignin “subway maps.” Both of these long-chain lignins are single molecules that have linked
many subunits together to form the overall final molecular conformation.
Recycling
All the phytochemicals discussed so far are produced by the cannabis plant itself. The
important starting molecules for phytochemical production in cannabis are acetyl CoA,
pyruvate, fatty acids (such as hexanoic acid), and small amino acids such as
phenylalanine. These small starting molecules are juggled by an array of enzymes to
produce larger molecules such as flavonoids, lignins, cannabinoids, and terpenes. The
ancestral cannabis plant evolved a preference for certain molecules that turned out to be
good starting points for synthesizing the multitude of other chemicals with broader
functions. The set of starting materials—the enzymes that transform those raw materials
and the steps required—are called pathways. The pathways to flavonoids, terpenes,
lignans, and cannabinoids are intricately intertwined with each other, producing a
spaghetti-like picture of phytochemical production. Since cannabis relies on all these
phytochemicals for its characteristics, the picture of cannabis secondary compound
synthesis is particularly convoluted and sticky.
