Overview of Cytochrome P450 2B1

Cytochrome P450 2B1 is an enzyme containing heme as a cofactor that functions primarily, but not exclusively, as a monooxygenase. Cytochrome P450 2B1 belongs to the cytochrome P450 superfamily, which is a group of enzymes involved in the metabolism of heterologous substances in the body. Cytochrome P450 2B1 is mainly expressed in the liver in mammals, accounting for 7% of the total liver cytochrome P450 protein. Cytochrome P450 2B1 participates in the NADPH-dependent electron transport pathway in liver microsomes and can oxidize a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The function and classification of cytochrome P450 2B1 is based on its metabolic capacity and affinity for different substrates. Cytochrome P450 2B1 can be divided into two subtypes: CYP2B1 and CYP2B2, which share more than 90% amino acid sequence similarity. CYP2B1 is mainly involved in the metabolism of polycyclic aromatic hydrocarbon carcinogens, while CYP2B2 is mainly involved in the metabolism of drugs such as phenobarbital and ciprofloxacin.

Cytochrome P450 2B1 is of great significance in the treatment of diseases, because it can affect the efficacy and safety of drugs, and can also participate in the occurrence and development of some diseases. Cytochrome P450 2B1 can convert the drug into a more excretable or more active form through reactions such as oxidation, reduction or hydrolysis, thereby changing the concentration and action time of the drug in the body. Cytochrome P450 2B1 can also convert some non-toxic or low-toxic compounds into toxic or carcinogenic metabolites, which can lead to diseases such as liver damage or cancer. In addition, cytochrome P450 2B1 can also metabolize some endogenous or exogenous hormones, affect hormone levels and signal transduction, and thus involve in diseases such as metabolic syndrome, hypertension and cancer.

Relationship Between Cytochrome P450 2B1 and Diseases

The mechanism of action of cytochrome P450 2B1 in diseases such as liver injury, metabolic syndrome, hypertension and cancer is by participating in the metabolism of drugs or endogenous substances related to these diseases, thereby affecting their efficacy and safety, and regulating Several signaling pathways or gene expression, thereby affecting the function and structure of the liver.

In liver injury, cytochrome P450 2B1 can metabolize some drugs or chemicals that cause hepatotoxicity, such as ethanol, acetaminophen, carbon tetrachloride. These substances are metabolized by cytochrome P450 2B1 to produce active or toxic metabolites, such as acetaldehyde, N-acetanilide quinone, trichloromethyl free radical. These metabolites can cause oxidative stress, lipid peroxidation, mitochondrial damage, imbalance of calcium homeostasis, apoptosis or necrosis in hepatocytes, leading to liver damage. On the other hand, cytochrome P450 2B1 can also metabolize some protective drugs or chemicals, such as acetophenone, butanone, and tea polyphenols. These substances are metabolized by cytochrome P450 2B1 to produce metabolites with antioxidant or anti-inflammatory effects, such as tea polyphenols and 4-hydroxyphenethylamine. These metabolites can inhibit oxidative stress, lipid peroxidation, mitochondrial damage, imbalance of calcium homeostasis, apoptosis or necrosis in hepatocytes, thereby protecting the liver from damage.

In metabolic syndrome, cytochrome P450 2B1 can metabolize some drugs or endogenous substances that affect blood sugar and blood lipid levels, such as acetophenone, methyl ethyl ketone, insulin. These substances are metabolized by cytochrome P450 2B1 to produce metabolites that regulate blood sugar and blood lipid levels, such as 4-hydroxyphenethylamine and 3-hydroxybutyric acid. These metabolites can increase insulin sensitivity, promote glucose uptake and utilization, inhibit fat synthesis and deposition, etc., thereby improving the symptoms of metabolic syndrome. On the other hand, cytochrome P450 2B1 can also metabolize some drugs or endogenous substances that induce or aggravate metabolic syndrome, such as phenobarbital, rifampicin, and nicotine. These substances are metabolized by cytochrome P450 2B1 to produce metabolites that interfere with blood sugar and blood lipid levels, such as 4-hydroxymethamphetamine and 4-hydroxyphenethylamine. These metabolites can reduce insulin sensitivity, inhibit glucose uptake and utilization, promote fat synthesis and deposition, thereby exacerbating the symptoms of metabolic syndrome.

In hypertension, cytochrome P450 2B1 can metabolize some drugs or endogenous substances that affect blood pressure regulation, such as diuretics, β-blockers, and arachidonic acid. These substances are metabolized by cytochrome P450 2B1 to produce metabolites such as 20-hydroxyarachidonic acid (20-HETE) that regulate blood pressure. These metabolites can regulate blood pressure by affecting the contraction or relaxation of vascular smooth muscle cells, sodium levels in the kidney, or the renin-angiotensin system, among others. On the other hand, cytochrome P450 2B1 can also metabolize some drugs or endogenous substances that induce or aggravate hypertension, such as ethanol, nicotine, and nitrous oxide. These substances are metabolized by cytochrome P450 2B1 to produce metabolites that interfere with blood pressure, such as acetaldehyde, 4-hydroxymethamphetamine, and nitrite. These metabolites can increase blood pressure by affecting the contraction or relaxation of vascular smooth muscle cells, sodium levels in the kidney, or the renin-angiotensin system, among others.

In cancer, cytochrome P450 2B1 can metabolize some anticancer drugs or endogenous substances, such as cyclophosphamide, isocyclic citric acid, and tea polyphenols. These substances are metabolized by cytochrome P450 2B1 to produce metabolites with anticancer effects, such as 4-hydroxycyclophosphamide, isocyclic citrate diester, and tea polyphenols. These metabolites can inhibit the development of cancer by inducing apoptosis or necrosis of cancer cells, inhibiting the proliferation or invasion of cancer cells, regulating the signaling pathways or gene expression of cancer cells, etc. On the other hand, cytochrome P450 2B1 can also metabolize some carcinogenic drugs or endogenous substances, such as nicotine, benzopyrene, and nitrosamines. These substances are metabolized by cytochrome P450 2B1 to produce carcinogenic metabolites, such as 4-hydroxymethamphetamine, benzopyrene, and nitrosamines. These metabolites can promote the development of cancer by inducing the mutation or aberration of cancer cells, promoting the proliferation or invasion of cancer cells, regulating the signaling pathways or gene expression of cancer cells.

The Role of Cytochrome P450 2B1 in Drug Metabolism

The role of cytochrome P450 2B1 in drug metabolism is to convert drugs or other xenobiotics into more easily excreted water-soluble metabolites through oxidation reactions. cytochrome P450 2B1 can metabolize a variety of drugs, such as phenobarbital, rifampicin, nicotine, methamphetamine. The impact of cytochrome P450 2B1 on drug efficacy and safety mainly depends on the pharmacokinetic and pharmacodynamic properties of the drug.

If a drug is a substrate of cytochrome P450 2B1, that is. its metabolism is largely dependent on the cytochrome P450 2B1 enzyme, then the activity or expression level of cytochrome P450 2B1 can affect the plasma concentration and half-life of the drug. In general, the higher the activity or expression level of cytochrome P450 2B1, the lower the plasma concentration and half-life of the drug, and vice versa. This means that the activity or expression level of cytochrome P450 2B1 can affect the efficacy and toxicity of drugs. For example, rifampicin, an anti-tuberculosis drug, is also a substrate and inducer of cytochrome P450 2B1. Rifampicin can increase the activity or expression level of cytochrome P450 2B1, thereby accelerating the metabolism of itself and other cytochrome P450 2B1 substrates, resulting in a decrease in its plasma concentration, thereby reducing its effect or increasing its tolerance.

If a drug is a product of cytochrome P450 2B1, that is, its metabolism to produce active or toxic metabolites is primarily dependent on cytochrome P450 2B1 enzymes, the activity or expression level of cytochrome P450 2B1 can affect the plasma concentration and half-life of the drug's metabolites. In general, the higher the activity or expression level of cytochrome P450 2B1, the higher the plasma concentration and half-life of the drug's metabolites, and vice versa. This means that the activity or expression level of cytochrome P450 2B1 can affect the efficacy and toxicity of drugs. For example, methamphetamine, a central nervous system stimulant, is also a product of cytochrome P450 2B1. Methamphetamine is metabolized by cytochrome P450 2B1 to 4-hydroxymethamphetamine (4-HMA) and 4-hydroxyphenethylamine (4-HA), two metabolites that are neurotoxic and hepatotoxic. Therefore, the higher the activity or expression level of cytochrome P450 2B1, the higher the neurotoxicity and hepatotoxicity of methamphetamine.

If a drug is both a cytochrome P450 2B1 substrate and a cytochrome P450 2B1 product, that is, its metabolism depends on cytochrome P450 2B1 enzymes and produces cytochrome P450 2B1 enzyme-dependent activity or toxic metabolites, then the activity or expression level of cytochrome P450 2B1 will affect both the drug and its metabolites. Plasma concentration and half-life, thereby affecting drug efficacy and toxicity. For example, nicotine, an addictive substance in tobacco, is also a substrate and product of cytochrome P450 2B1. Nicotine is metabolized by cytochrome P450 2B1 to generate carcinogenic nitrosamine compounds, such as 4-(methylenenitroso)-1-(3-pyridyl)-1-butanol (NNK) and N-nitroso- 3-picolylamine (NNA). Thus, the higher the activity or expression level of cytochrome P450 2B1, the lower the plasma concentration of nicotine, but the higher the plasma concentration of its oncogenic metabolites.

The purpose of individualized drug therapy using cytochrome P450 2B1 is to adjust the dose or selection of drugs according to the cytochrome P450 2B1 genotype or phenotype of different individuals or groups, so as to achieve the best efficacy and minimum toxicity. To achieve this, the detection and analysis of cytochrome P450 2B1 genotype or phenotype in different individuals or populations, as well as the assessment of cytochrome P450 2B1 dependence of different drugs are required. At present, some methods can be used to detect and analyze cytochrome P450 2B1 genotype or phenotype, such as genotyping, enzyme activity detection, biomarker analysis. At the same time, there are also some methods that can be used to assess the cytochrome P450 2B1 dependence of different drugs, such as pharmacokinetic models, pharmacodynamic models, pharmacokinetic-pharmacodynamic correlation models. Through these methods, individualized drug treatment recommendations can be provided for different individuals or groups, thereby improving the efficiency and safety of drug treatment.

Regulatory Mechanism of Cytochrome P450 2B1

The activity of cytochrome P450 2B1 is influenced by multiple factors, including inducers, inhibitors, genetic polymorphisms, and environmental factors. An inducer is a substance that increases the expression or activity of cytochrome P450 2B1, thereby accelerating the rate at which cytochrome P450 2B1 metabolizes xenobiotics. Some common cytochrome P450 2B1 inducers include Phenobarbitals, rifampicin, carbamazepine, etc. These inducers regulate the gene expression of cytochrome P450 2B1 by activating transcription factors such as nuclear receptors. For example, rifampin activates hepatocyte nuclear factor 4α (HNF4α) and pregnane X receptor (PXR), thereby increasing the transcription of cytochrome P450 2B1. The action of inducers can reduce the plasma concentration of drugs metabolized by cytochrome P450 2B1, thereby reducing the effect of the drug or increasing drug tolerance. An inhibitor is a substance that reduces the expression or activity of cytochrome P450 2B1, thereby reducing the rate at which cytochrome P450 2B1 metabolizes xenobiotics. Some common cytochrome P450 2B1 inhibitors include clopidogrel, ketoconazole, teclopyridine, and others. These inhibitors work by binding competitively or non-competitively to the active site of cytochrome P450 2B1, preventing it from binding substrates or catalyzing reactions. The action of inhibitors can increase the plasma concentration of drugs metabolized by cytochrome P450 2B1, thereby increasing the effect or toxicity of the drug.

Table 1. Inducers of Cytochrome P450 2B1

Table 2. Inhibitors of Cytochrome P450 2B1

Gene polymorphism refers to the genetic variation of the cytochrome P450 2B1 gene in different individuals or populations, resulting in differences in the structure or function of the cytochrome P450 2B1 enzyme. There are several known cytochrome P450 2B1 genetic variants that affect the expression level or activity of the cytochrome P450 2B1 enzyme, thereby affecting its ability to metabolize drugs or other xenobiotics. For example, CYP2B66 variants reduce the expression and activity of the cytochrome P450 2B1 enzyme, resulting in slower metabolism of drugs such as nicotine and methamphetamine, thereby increasing their plasma concentrations and toxicity. Environmental factors refer to the influence of the outside world on the activity or expression of cytochrome P450 2B1 enzymes, including diet, living habits, disease states. Several environmental factors can alter the function or stability of cytochrome P450 2B1 enzymes, thereby affecting their ability to metabolize drugs or other xenobiotics. For example, compounds contained in some foods or drinks, such as naringin in grapefruit, can inhibit the activity of the cytochrome P450 2B1 enzyme, thereby increasing the plasma concentration and toxicity of some drugs (such as cimetidine, diazepam). On the other hand, some disease states, such as hepatitis, cirrhosis, liver cancer, can reduce the expression or activity of cytochrome P450 2B1 enzyme, thereby reducing the metabolism and clearance of some drugs (such as phenobarbital, rifampin).