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TETRAHIDROCANNABINOL (THC), GENETIC VARIABILITY AND VARIABILITY IN PHARMACOLOGICAL RESPONSE
The most frequent drug of consumption in the world is marijuana, with a 3.8% prevalence (around 183 million people), followed by amphetamines and amphetamine-type stimulants(1) .
In Mexico, there is an estimated 14.0% of men and 3.7% of women who uses it; Additionally, it is the drug with the highest increase in consumption, both in men and women. The risk perception of marijuana use is involved in this growth, it has fallen below 40%, while in other substances such as cocaine or inhalants it reaches values above 62%(2) .
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Cannabis is a plant native to Mongolia and southern Siberia. America’s first contact with it was through Christopher Columbus, who transported in his boats an estimated 80 tons of sails and ropes made of hemp. Later, during the conquest period (~ 1521), Hernán Cortés imported several plants from Europe and Asia, including C. sativa and C. indica, to boost the economy of New Spain(3) .
The Cannabis Sativa plant belongs to the Cannabaceae family (4), it is composed for more than 545 substances (5) from 18 types of chemical compounds (4), where at least 120 phytocannabinoids have been identified (6) .
Phytocannabinoids can be divided into 11 classes, depending on their chemical structure: cannabigerol, (-) - 19-tetrahydrocannabinol, cannabidiol, cannabichromene, cannabinol, (-) - 18 tetrahydrocannabinol, cannabicyclol, cannabinodiol, cannabielsoin, cannabitriol and miscellaneous (7). Most of the biological properties of cannabinoids lie in their interaction with the human endocannabinoid system. This system includes two G protein coupled to cannabinoid receptors, CB1 and CB2, as well as two endogenous ligands, anandamide and 2-arachidonylglycerol (8).
Among cannabinoids, Δ9-Tetrahydrocannabinol (THC) has the highest psychoactive strenght(9). It has shown analgesic, immunosuppressive and muscle relaxant, antiinflammatory, appetite modulator, antidepressant, antiemetic, bronchodilator, neuroleptic, antineoplastic and antiallergen effects (10); however, it has also been associated with some side effects, including anxiety, cholinergic deficit, severe immunosuppression, hallucinations, paranoia, and tachycardia. These adverse effects have been commonly associated with car accidents, work injuries, and hospitalizations (11) .
The primary metabolic pathway for THC involves cytochrome CYP2C9. THC hydroxylates to its active form (OH-THC) still with significant psychoactive activity, it is later oxidized by CYP2C9 to its acidic carboxylic form (COOH-THC), which is pharmacologically inactive (11) .
Cytochromes P450 (CYP 450) constitute a family of hemoproteins found in organisms from all biological kingdoms, from bacteria to mammals. In humans, 18 families and 48 subfamilies of CYP450 have been described, encoded by 57 genes expressed in different organs and tissues. In the nomenclature of these cytochromes, the number followed by CYP designates the family, the letter the subfamily and the number the gene (CYP1A1, CYP2E1) (12) .
Families 1, 2 and 3 include the enzymes responsible for biotransforming xenobiotics. Only CYP1A, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 metabolize 90% of the drugs for human use (12) .
CYP2C9 is one of the most abundant enzymes in the adult human liver, it metabolizes a significant number of drugs: cannabinoids, antibiotics, anticancer, antidiabetic, antiepileptic, antihypertensive, among others (13); this corresponds to 10 %-20% of the commonly prescribed drugs (14). To date, 42 alleles have been identified in the CYP2C9 gene (13) .
Polymorphisms with reduced activity increase the risk of toxicity and side effects (15). The CYP2C9 * 2 variant is the most prevalent and has been suggested to affect the P450 interaction between the enzyme and P450 reductase; this could explain the slow metabolism of some CYP2C9 substrates (13) (enzyme activity of 12% compared to the wild variant) (16) .
Genetic epidemiology trials have shown that 15-20% of the population has the CYP2C9 * 3 allele. This gene variant results in a much slower communication of THC with its non-psychoactive form compared to the “normal” CYP2C9 * 1 allele’s variant. Therefore, individuals with * 3 allele can accumulate THC levels 200-300% higher than those with the normal allele (11) .
The frequencies of allelic variants of the CYP2C9 gene differ depending on the population. The CYP2C9 * 2 polymorphism in the European population occurs at a frequency of 16% in Spaniards, 10.7% in Swedes, 12.5% in British, and 11.2% in Italians; this frequency is very similar to that reported in Americans (15%). In the East Asian population, this polymorphism is considered rare as it occurs at a frequency ≤ 0.1% (17) .
CYP2C9 * 3 presents less frequently than CYP2C9 * 2. The highest frequency of this polymorphism is observed in Europeans (7.4-9.2%), also in Iranians (9.7%) and Turks (10%) in West Asia. The frequency of this polymorphism in East Asia widely varies, Chinese population presents a greater frequency compared to Japanese and Koreans. In the Mexican population, this polymorphism is observed in 1.5% of the Mexican-Tepehuano and Mexicomestizo population and in 6% of the Mexican-American population (17) .
An important characteristic in the Mexican population is the miscegenation between the Amerindian and Caucasian groups from Europe and Africans brought in as slaves in the 16th century as a result of the conquest (14). In addition to the mestizo population, it is of note that in Mexico there are currently 70 indigenous groups that represent 6.1% of the total population (18). Due to this particularity, it is necessary to know which alleles are present in our population and what are their frequency in order to find out the relationship and efficacy of the drugs prescribed.
In Mexico, pharmacogenomics has not yet been fully extended to the daily clinical practice; there are however different research groups that have taken on the task of elucidating genetic variations within our population.
The following graph shows different pharmacokinetic curves that may present the same dose of THC, given by the variations in CYP isoforms, in such a way that low doses of THC will yield in some people levels resulting in unwanted side effects, while the expected effect will be attained in people who metabolize it in a “normal” way.
Concentration (ng/mL)
Time (hrs)
It is estimated that genetics explains 20 to 95% of the variability in the disposition and effects of drugs (19), including THC; thus, knowing the frequency of genetic variants within populations will lead to predictive applications and more effective treatments.
BIBLIOGRAPHY:
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Javier Esquivel Vargas, Diana Vega Perea, Darío Morales Martínez, Miriam Morales Mtz., Alberto García González, Alionka Citlali P. Ángeles
