Introduction to Human Cytochrome P450 Superfamily
Shufeng Zhou in Cytochrome P450 2D6, 2018
Gellner et al. (2001) have found that, on chromosome 7q21.1, where the CYP3A4 gene had previously been mapped, there is a 231-kb region containing three CYP3A genes: CYP3A4, 3A5, and 3A7, as well as two pseudogenes (CYP3A5P1 and 3A5P2) and another CYP3A gene, which they termed CYP3A43. The CYP3A subfamily, CYP3A4, 3A5, 3A7 and 3A43, is one of the most versatile of the enzyme systems that are responsible for the elimination of 37% of drugs out of the 200 most frequently prescribed drugs in the United States. CYP3A4 and 3A5 together account for approximately 30% of total hepatic CYPs, and approximately half of the drugs that are oxidatively metabolized by CYPs are CYP3A substrates. Both CYP3A4 and 3A5 are expressed in the liver and intestine, with CYP3A5 being the predominant form expressed in extrahepatic tissues. CYP3A4 is the most abundantly expressed form in the liver while CYP3A5 expression at the protein level is only approximately 10.6% of that of CYP3A4 (Wang and Tompkins 2008). CYP3A7 is considered a fetal-specific CYP enzyme, and CYP3A43 has extremely low expression in the liver and only plays a minor role in drug metabolism.
Drug Repurposing and Novel Antiviral Drugs for COVID-19 Management
Debmalya Barh, Kenneth Lundstrom in COVID-19, 2022
In an attempt to solve the puzzle, the WHO embarked on an ambitious global “mega-trial” called SOLIDARITY in January 2020. In the trial, confirmed cases of COVD-19 were randomized to standard care or one of four active treatment arms (remdesivir, CQ or HCQ, lopinavir/ritonavir, or lopinavir/ritonavir plus interferon beta-1a). In early July 2020, the treatment arms in hospitalized patients that included HCQ, CQ, or lopinavir/ritonavir were discontinued. Interim results released in mid-October 2020 stated that the four aforementioned repurposed antiviral agents appeared to have little or no effect on hospitalized patients with COVID-19 in comparison to standard care, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay [10]. With weak evidence and theoretically unfavorable pharmacodynamics the NIH Panel for COVID-19 Treatment Guidelines and Infectious Diseases Society of America (IDSA) did not recommend use of lopinavir/ritonavir or any other HIV protease inhibitors for the treatment of COVID-19 patients. IDSA also mentioned that CYP3A inhibition can result in increased risk of severe cutaneous reactions, QT prolongation, and potential drug interactions. Various combinations of methylprednisolone with umifenovir or lopinavir/ritonavir are still being studied to improve the treatment outcomes [11].
Role of Genetic Variability in Breast Cancer Treatment Outcomes
Brian Leyland-Jones in Pharmacogenetics of Breast Cancer, 2020
CYP3A4 also plays a large role in the metabolism of CP, and the CYP3A4 gene has a number of known variant alleles, including some having functional significance (19). A single base substitution in the 5’ promoter region of the gene (20), present in 9% of European-Americans and 53% of African-Americans (21), with the CYP3A4*1B allele associated with expression levels is 1.4-fold higher than that in common alleles (22). Using enzyme kinetic analyses to evaluate intersample variation in activation of CP by CYP3A and 2B in human liver, both Chang et al. (1993) and Roy et al. (1999) found considerable interindividual differences in CYP3A and CYP2B levels and variation over a wide range in CP hydroxylation (10,23). Variation in CYP3A enzyme levels and expression may be related, in part, to genetic differences or to other chemotherapeutic and natural agents that have been shown to increase CYP3A4 expression (24).
In vitro effects of peimine on the activity of cytochrome P450 enzymes
Published in Xenobiotica, 2020
Meng Li, Xiaoyan Liu, Yuzhen Wang, Xiuli Ju
CYP3A is a family, including four enzymes that participate in the metabolism of a variety of drugs (Basheer & Kerem, 2015; Srinivas, 2016). Among the CYP3A family, CYP3A4 plays an important role, because most of the CYP3A cleared drugs have been largely ascribed to the activity of CYP3A4. The inhibition of CYP3A4 activity could influence the pharmacokinetics of drugs, which are metabolized by CYP3A4 and then induce potential drug-drug interaction. Therefore, peimine should be used carefully, especially co-administrated with drugs metabolized by CYP3A4 in the clinic. On the other hand, CYP3A5 can also contribute to a similar function to CYP3A4 (Lamba et al., 2002). The previous study has reported that some drugs or inhibitors which could exert inhibitory effects on the activity of CYP3A4, could also inhibit the activity of CYP3A5 (Jin et al., 2007; Tseng et al., 2014). The activity of CYP3A5 was neglected, and further study should pay more attention to the interaction between peimine and CYP3A5.
In vitro inhibitory effects of ganoderic acid A on human liver cytochrome P450 enzymes
Published in Pharmaceutical Biology, 2020
Shangchen Xu, Fengqing Zhang, Dali Chen, Keren Su, Li Zhang, Rui Jiang
The results of the enzyme inhibition and kinetic studies showed the inhibitory effect of GAA on the activity of CYP3A4, 2D6, and 2E1. CYP3A is the most important drug metabolizing enzymes involved in drug clearance (Evans and Relling 1999). The CYP3A family of enzymes includes CYP3A4, 3A5, 3A7, and 3A4. Most of the CYP3A cleared drugs have been largely ascribed to the activity of CYP3A4, therefore, the effect on the activity of CYP3A4 will directly affect the clearance of most drugs metabolized by CYP3A. GAA inhibited the activity of CYP3A4 in a non-competitive manner, and the inhibition was increased with the incubation time. These results indicated that the dosage concentration and medication time of the drugs metabolized by CYP3A4 should be paid special attention, when combined with GAA. Moreover, among the CYP3A family, CYP3A5 can also contribute to the similar function to CYP3A4 (Lamba et al. 2002). Previous study has reported that some drugs or inhibitors which could exert inhibitory effect on the activity of CYP3A4, could also inhibit the activity of CYP3A5 (Jin et al. 2007; Tseng et al. 2014). Therefore, the drugs of which the metabolism is mediated by CYP3A5 should also be carefully used with GAA. Meanwhile, the effect of GAA on the activity of CYP3A5 needs further investigations to provide direct evidence.
The effect of co-administration of berberine, resveratrol, and glibenclamide on xenobiotic metabolizing enzyme activities in diabetic rat liver
Published in Drug and Chemical Toxicology, 2022
Azra Bozcaarmutlu, Canan Sapmaz, Ömer Bozdoğan, Aysel Kükner, Leyla Kılınç, Salih Tunç Kaya, Oğulcan Talat Özarslan, Didem Ekşioğlu
Co-administration of R+B in the diabetic rats decreased CYP2B-associated PROD activity to the non-diabetic control activity level. Co-administration of R+G and R+B in diabetic rats significantly decreased CYP3A-associated ERND activities compared to the non-diabetic control group. CYP3A is responsible for the metabolism of both endogenous and exogenous molecules such as drugs. Similarly, GST activities of D+R+G and D+R+B groups were less than the non-diabetic control group. Glutathione S-transferases are also responsible for the elimination of many exogenous molecules and they generally catalyze detoxification reactions. Co-administration of these chemicals may inhibit the metabolism of endogenous and exogenous molecules and may cause a toxic reaction by inhibiting the metabolism of drugs metabolized by CYP3A and GST.
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