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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
The CYP3A subfamily consists of at least 4 enzymes: CYP3A4, CYP3A5, CYP3A7 and CYP3A43. CYP3A4/CYP3A5 account for 30 to 40% of total CYP content in the adult liver and intestine. CYP3A4 and CYP3A5 are differentially expressed, but have largely overlapping substrate specificity. CYP3A7 is the main CYP isoform in the human fetal and newborn liver. From the few studies available, it appears that the substrate specificity of CYP3A7 is different from CYP3A4.
Combined methods
Published in Suzanne Everett, Handbook of Contraception and Sexual Health, 2020
New research has found that in a study of 350 women 5% had a gene called CYP3A7*1C enzyme. CYP3A*1C is usually active in foetuses and then switched off at birth. CYPSA7*1C has been found to break down hormonal contraception and may affect contraceptive efficacy. Further research is needed to help the understand the implications (Lazorwitz et al., 2019).
Ergot Alkaloids
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Given that ergot alkaloids are not destroyed by milling and baking, consumption of bread made from ergot-contaminated grains leads to intake of ergot alkaloids, which are transported passively or actively across the gastrointestinal epithelia, and move via the lymphatic system or bloodstream to the liver and other organs and tissues [25]. In mammals, biotransformation of ergot alkaloids is mediated primarily by the CYP3A subfamily of cytochrome P450 enzyme systems. Of the three genes (CYP3A4, CYP3A5, and CYP3A7) in the CYP3A subfamily, CYP3A4 is actively involved in xenobiotic metabolism human liver and intestine [26]. Mutations in the CYP3A4 gene may increase human susceptibility to ergot alkaloid intoxication [27]. Elimination of alkaloids in humans appears to take place in two phases, with the α-phase corresponding to whole-body elimination and tissue distribution (half-life of 1.5–6.2 hours), and the β-phase corresponding to whole-body elimination only (half-life of 16–31 hours).
Effect of formulation and route of administration on the distribution of 17-hydroxyprogesterone caproate in rats
Published in Xenobiotica, 2023
Imam H. Shaik, Nupur Chaphekar, Vignesh Vasudevan, Ali Alshabi, Jaime R. Bastian, Wenchen Zhao, Steve Caritis, Raman Venkataramanan
Previous reports from our group (using human hepatocyte cultures and human liver microsomes) have identified that CYP3A4 primarily contributes to the metabolism of 17-OHPC but CYP3A7 (the foetal form of CYP3A4) is also involved in the metabolism of 17-OHPC based on studies in foetal hepatocytes (Sharma et al. 2010). Metabolic studies of human liver microsomes and expressed enzyme systems show that CYP3A4 and CYP3A5 metabolise 17-OHPC (Sharma et al. 2008). The metabolism of 17-OHPC by hepatic microsomes of humans and baboons suggested the formation of mono-, di-, and tri-hydroxylated derivatives of 17-OHPC. The metabolism of 17-OHPC by placental microsomes (Human and Baboons) result in the formation of mono-hydroxylated derivatives of 17-OHPC (Yan et al. 2008). 17-OHPC at higher concentrations appears to inhibit ABCB11 in transporter in studies using adult female hepatocytes, but the activity was not affected at concentrations observed in patients (Sharma et al. 2013).
Metabolism of the antipsychotic drug olanzapine by CYP3A43
Published in Xenobiotica, 2022
Jie Zhao, David Machalz, Sijie Liu, Clemens Alexander Wolf, Gerhard Wolber, Maria Kristina Parr, Matthias Bureik
CYP3A43 is one of four members of the human CYP3A family, which together metabolise a large percentage of xenobiotics in the human body (Nebert et al. 2013). Within this family, CYP3A4 is by far the best-studied enzyme, followed by CYP3A5 and CYP3A7 (in this order) (Machalz et al. 2021). By contrast, CYP3A43 has not yet been well characterised. In one study low but detectable testosterone 6β-hydroxylation activity of CYP3A43 was observed, being about two orders of magnitude lower than that of CYP3A4 (Domanski et al. 2001). Another publication described the metabolism of the anti-anxiety drug alprazolam to both α-hydroxyalprazolam (the active metabolite) and 4-hydroxyalprazolam (an inactive metabolite) by CYP3A43, while CYP3A4 only produces the latter (Agarwal et al. 2008). Very recently we reported the biotransformation of a proluciferin probe substrate (Luciferin 6′ 4-fluorobenzyl ether methyl ester, 4FBEME) by CYP3A43 (Sharma et al. 2021). No other activities of CYP3A43 have been described to date. Data from the Genotype-Tissue Expression (GTEx) Project show that the expression of this gene is strongest in the liver, pancreas, testis, and prostate; signals are detectable in the brain but levels are very low. Both the known activity data and the expression pattern (Supplementary Figure 1) suggest that like the other CYP3A enzymes, CYP3A43 is involved in the metabolism of endogenous as well as xenobiotic compounds.
Impact of DNA methylation on ADME gene expression, drug disposition, and efficacy
Published in Drug Metabolism Reviews, 2022
Xu Hao, Yuanyuan Li, Jialu Bian, Ying Zhang, Shiyu He, Feng Yu, Yufei Feng, Lin Huang
The CYP1A1 gene expression significantly increased in cancerous tissues compared to their normal tissue cohort and is significantly associated with hypomethylation at the CpG site −1383 (p = 0.018) within the XRE10 motif (Sadeghi-Amiri et al. 2021). Tsai et al. identified CYP1A1 (cg23680900, cg26516004, cg10009577, cg23160522, cg00353139) and CYP1B1 (cg20408276) which were both hypomethylated and upregulated in current smokers (Tsai et al. 2018). In the full set of prenatal and postnatal liver samples, the expression of CYP3A7 was inversely correlated with methylation of CYP3A7 (−219), CYP3A7 (−199), and CYP3A7 (−182). CYP3A4 expression was inversely correlated with methylation of CYP3A4 (−383), and positively correlated with methylation of CYP3A4 (−667), CYP3A4 (−1452), CYP3A4 (−1521), CYP3A4 (−1547), CYP3A4 (−1569) (Vyhlidal et al. 2016). Critical genes in the vitamin D signaling system, such as CYP2R1 (−20 to +850), CYP27B1 (+976 to +2120), and CYP24A1 (−470 to +1263) have large CpG islands in their promoter regions and therefore can be silenced by DNA methylation (Fetahu et al. 2014). The DPYD promoter region (−145 to +16) contains 27 CpG sites, which was related to gene expression (Zhang et al. 2007). The Cancer Genome Atlas showed GPX3 hypermethylation (cg21504918) and an inverse correlation between GPX3 methylation and expression (Zhou et al. 2019).