What Is Genetic Pharming?

Pharmacogenetics is a marginal subject combining pharmacology and genetics. It studies the influence of genetic factors on drug metabolism, especially the abnormal drug response caused by genetic factors. The study of pharmacogenetics has enriched the content of human genetics and has great significance for clinical medicine.

Pharmacogenetics

Pharmacogenetics is

It studies the influence of genetic factors on pharmacokinetics, especially in the role of abnormal drug reactions. Clinicians must follow the principle of different medicines when using certain medicines. Because in a population, different individuals may have different reactions to a certain drug, and may even have serious adverse side effects, this phenomenon is called individual idiosyncracy. The cause of atopy depends in large part on the genetic background of the individual.

Drugs must be absorbed, distributed, metabolized, and excreted in the body to complete the process of drug effects. In this process, many links are closely related to the role of enzymes and receptors. If there are mutations or defects in the genes that determine these enzymes or receptor proteins, it will inevitably lead to abnormal reactions in drug metabolism. Therefore, it is necessary to understand the influence of genetic variation on drug response and its molecular basis, and predict individuals who respond to drug abnormalities accordingly, so as to carry out effective prevention and treatment. The research on pharmacogenetics has revealed the genetic basis and biochemical nature of many abnormal drug reactions, which has guiding value for guiding clinicians to correctly grasp the individualized principles of medication and prevent various genetic-related drug reactions.

People have long found that some people are extremely sensitive to certain drugs (such as antimalarials, etc.), and abnormal drug reactions (such as rash, hemolysis, etc.) occur when taking regular doses.

In 1957, A.G. Motulsky first pointed out that certain abnormal drug responses were related to genetic defects.

In 1959 T. Fogel formally proposed the name pharmacogenetics.

In 1962 W. Carlow published a book related to pharmacogenetics.

In 1973, the World Health Organization published a technical report on pharmacogenetics, which reviewed the basic content of pharmacogenetics.

The main research content of pharmacogenetics is the genetic basis of abnormal drug response. Single-gene heredity plays a major role in many factors (including physiological status, gender, age, genetics, and environmental factors) that cause individual differences in drug responses. The abnormal drug response caused by genetic factors is essentially

Drug use should vary from person to person. After taking the same standard dose of drugs, some people have poor efficacy due to fast drug metabolism and low drug concentration in plasma. Most people have normal drug metabolism and effective drug concentrations in plasma have significant effects. Drug metabolism is slow and the plasma drug concentration is too high, which may cause symptoms of poisoning. Therefore, the use of drugs should be based on the patient's genetic characteristics, the establishment of individualized principles of drug use, so as to improve drug efficacy and reduce or avoid adverse drug reactions.

For people with a family history of genetic defects in drug metabolism, care should be taken when using sensitive drugs, such as antimalarial, antipyretic and analgesic drugs and sulfa drugs for people with a family history of G6PD deficiency. So as not to cause hemolytic reactions. For people with a family history of malignant hyperthermia caused by drugs, the activity of phosphocreatine kinase (CPK) in their serum should be tested before using anesthetic to avoid accidents. According to the characteristics of drug genetics, preclinical patients can also be detected. For example, when dexamethasone is used to point the eye of a patient, if the intraocular pressure is found to be elevated, it means that the patient may be a glaucoma patient or a preclinical type of glaucoma.

The history of pharmacogenetics research is not long. Although there are many obvious single-gene hereditary traits of drug heredity, the metabolic characteristics of some commonly used drugs (such as cardiotonics, antipyretic and analgesics, etc.) are not systematically studied. Pharmacogenetics research.

Traditional pharmacogenetics

Pharmacogenetics includes pharmacokinetics and pharmacodynamics. Pharmacokinetic effects are caused by differences in the absorption, distribution, metabolism (including the activation of prodrugs, the inactivation of active molecules, and the production of biologically active derivatives of drugs) or excretion among individuals between drugs. Inappropriate drug concentrations or metabolites can lead to reduced efficacy or toxic side effects.

Pharmacogenetics has been linked to pharmacokinetics for more than 100 years, and its creation is attributed to the discovery of a class of mental patients who develop porphyria after treatment with the hypnotic agent diethylsulfopropane. Since then, we have known that the different activities of the enzymes are genetically caused, mainly related to the P450 enzyme family (Tables 2, 3). In addition, pharmacokinetic effects are also related to transmembrane transfer substances. For example, the different activities of MDR-1 genetic variants can affect the effective intracellular concentration of antiretroviral drugs or purine analogs, thiomethylalanine.

Although it has been known that the metabolic activity of isoenzymes has been different since the mid-20th century, there is not much practical application and knowledge about this. The reason may be: on the one hand, when a relatively flat drug dose curve appears, the difference in the metabolic activity of isoenzymes has nothing to do with the pharmacokinetic effect; on the other hand, many drugs have many complex and parallel metabolic pathways, and sometimes an enzyme is not functional Another enzyme can make up for this deficiency. This compensated metabolic pathway may have different substrate affinities, but can maintain effective therapeutic concentrations of the drug in the plasma. Therefore, such polymorphisms are very limited in practical applications, and are basically limited to determining whether a thiopurine methyltransferase has a function-deficient mutation before chemotherapy with a purine analog.

In contrast, despite the appropriate drug concentration of the active drug at the site of action, pharmacodynamic effects will cause differences in drug effects between individuals. The target molecule of drug action or DNA mutation of target molecule metabolism pathway will affect the drug action. This applies primarily to palliative medicines, which improve symptoms by regulating pathways that are related to the phenotype of the disease, rather than being pathogenic. This pathway is not functionally defective, but can counteract the effects of dysfunctional pathogenesis-related pathways, thereby reducing disease symptoms.

A typical example is the use of beta-adrenergic blockers to treat hyperthyroidism. Although the sympathetic nervous system is not a causative factor for tachycardia and hypertension, buffering its baseline tension with epinephrine blockers before etiological therapy can reduce cardiovascular symptoms and signs. Most drugs in the pharmacopoeia are palliative medicines.

Let's take a hypothetical complex disease as an example. In this case, the dysfunction of one of the pathways controlling the trait leads to the disease. Blood pressure is a trait, while hypertension is a disease. A palliative therapy refers to the fact that although a dysfunctional pathway is the cause of the disease, if this pathway is determined by genetic variation rather than drug response, then pharmacogenetics and pharmacodynamics exist. If the mechanism of palliative drug action is related to molecular variation and there is not much physiological connection with the related phenotype, palliative therapy may not be effective. Regulating a pathway that is not very relevant to the disease in this case will not produce effective palliative care effects.

One of the most convincing examples is palliative care for asthma. Treatment of asthma relies on a series of drugs targeting different "genetic" pathways to relax the bronchi or produce anti-inflammatory effects, and often does not consider targeted therapies for the cause. One of the main methods of treating asthma is to activate B2-adrenergic receptors with special agonists, relax the bronchial smooth muscles and dilate the bronchial tubes. Recent studies have shown that several variants of the B2-adrenoceptor are associated with different therapeutic effects produced by B2-agonists. Patients with one or two copies of the glycine allele at arginine at position 16 had a 3- and 5-fold reduction in the efficacy of B2-agonists, respectively. In vivo and in vitro studies have shown that this condition is related to the enhancement rate of agonist-induced receptor downregulation, and not to the transcriptional or translational differences of the gene and the binding of agonists. In contrast, the second polymorphism is at position 19 of the beta upstream peptide, which affects the receptor's own translation (but does not affect transcription), reducing the number of receptors by 50%. This variant allele happens to be strongly imbalanced with the receptor's 16 variant allele. The presence of these two mutations at the same time will reduce the expression of B receptors and increase the down regulation of B receptors, thereby losing the efficacy of bronchodilator relaxation. It is important to note that there is no evidence that any allelic variation is associated with morbidity and thus pathogenicity.

Another approach to palliative treatment of asthma is to inhibit leukotriene synthesis. However, it has been clinically proven that the therapy is ineffective for a small number of patients with non-wild-type alleles in the promoter region of the 5-lipoxygenase gene. These allelic variants were previously thought to be associated with decreased gene transcriptional activity. It is clear that when 5-lipoxygenase activity decreases, the inhibitory effect of the drug may be ineffective. At present, there is no evidence that the 5-lipoxygenase gene mutation is the cause of asthma, and asthmatic patients and normal people carry this gene variant with the same frequency.

Pharmacogenetics can explain not only different pharmacodynamic effects, but also different side effects. An example is the pharmacogenetic relationship between variants of 12S rRNA (mitochondrial-encoded gene) and aminoglycoside-induced ototoxicity. Interestingly, gene mutations related to susceptibility to ototoxicity make human 12S rRNA gene sequences similar to bacterial 12S rRNA sequences, so human 12S rRNA has become a target for the action of aminoglycosides. In other cases, the 12S rRNA mutation itself does not cause side effects outside of treatment.