The eye
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
Congenital glaucoma may develop secondary to anterior segment malformation (Peters anomaly, Rieger syndrome, aniridia) and other generalised ocular problems (e.g. Sturge-Weber syndrome). When it is primary, a proportion of families appears to follow autosomal recessive inheritance, but isolated cases are much too common for this mode to explain all cases. The risk to sibs after a single affected child is around 10%; after two affected sibs, a 25% risk should be advised. Risks to children of affected individuals are uncertain. Assuming a mixture of recessive and polygenic forms, a risk of 5% seems appropriate until data are available. A specific cytochrome P450 gene on chromosome 2p, CYP1B1, has been shown to be responsible for some recessively inherited families, but other genetic loci also exist.
Cytochrome P450 Enzymes for the Synthesis of Novel and Known Drugs and Drug Metabolites
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
CYP19 is a mammalian aromatase, which can be targeted to develop drugs against hormone-responsive cancers. This enzyme is capable of transformation of androgens to estrogens, and reduction of the level of estrogen is an effective way to treat cancers (Guengerich, 2002). Letrozole and anastrazole are drugs that are manufactured based on this mechanism (Brodie, 1994). CYP3A4 can be targeted for developing drugs and prophylactic agents. One example for potent drug candidate development is based on inhibiting CYP3A4 to slow down the metabolism of expensive drugs. The goal is to use lower dose of the drug and to achieve better exposure in target organs (Guengerich, 2002). CYP3A4 is also a promising target for chemotherapeutic agents, e.g., gemcitabine, cisplatin, carboplatin, docetaxel, and paclitaxel used against non-small cell lung cancer (NSCLC). In-silico drug target interaction studies revealed better combination treatment regimen for advanced NSCLC using gemcitabine and carboplatin (Chun et al., 2001; Peter Guengerich et al., 2003; Subhani and Jamil, 2015). Same principle has been applied to CYP1B1. Inhibitors are developed targeting this enzyme, to block the activation of exogenous carcinogens, including estrogens 23, 24, and 25 (Langouet et al., 1995; Chun et al., 2001; Guengerich, 2002; Peter Guengerich et al., 2003). The applications of wild-type CYPs in production of drugs and drug metabolites are summarized in Table 14.1.
Alternative Tumor-Targeting Strategies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
In terms of the choice of enzyme, two examples of families that have been studied for this purpose are the matrix metallopeptidases (MMPs) and the P450s. The MMPs are calcium-dependent zinc-containing endopeptidases which degrade extracellular matrix components and remodel tissues, and are thought to play an important role in cancer progression and metastasis. The P450s are mixed function oxidases displaying selective aromatic hydroxylase activity. One family member, CYP1B1, is thought to be over-expressed in a wide variety of human tumors but not in normal tissues. Prodrugs sensitive to these two enzymes are still at the discovery stage and so are only just beginning to reach clinical evaluation.
Particulate matter less than 10 μm (PM10) activates cancer related genes in lung epithelial cells
Published in Inhalation Toxicology, 2020
Daeun Kang, In Beom Jung, Su Yel Lee, Se Jin Park, Sun Jung Kwon, Dong Ho Park, Ji Woong Son
Among the top 10 genes upregulated and downregulated genes in our study, those whose NGS and qRT-PCR results match are the CYP1A1, CYP1B1, LINC01816, and BPIFA2, as mentioned above. CYP1A1 and CYP1B1 encode a member of the cytochrome P450 superfamily of enzymes. The expression of CYP1A1 is induced by some polycyclic aromatic hydrocarbons (PAHs) or tobacco smoke, and they can metabolize some PAHs to carcinogenic intermediates (Shimada and Fujii-Kuriyama 2004). The expression can be regulated by heavy metal (Korashy and El-Kadi 2005; Anwar-Mohamed et al. 2009). There are many reports that CYP1A1 is linked to lung cancer. CYP1A1 can initiate carcinogenesis in lung cells through PAH metabolism (Uppstad et al. 2010). CYP1A1 plays an important role in lung DNA adduct formation and causes a higher susceptibility to lung cancer among women than men (Mollerup et al. 2006). Przygodzki et al. (1998) reported that CYP1A1 activation contributes to lung cancer via p53 inactivation. Some studies show that CYP1A1 polymorphism contributes to lung cancer susceptibility (Taioli et al. 2003; Ji et al. 2012).
Effect of inflammation on cytochrome P450-mediated arachidonic acid metabolism and the consequences on cardiac hypertrophy
Published in Drug Metabolism Reviews, 2023
Mohammed A. W. ElKhatib, Fadumo Ahmed Isse, Ayman O. S. El-Kadi
Multiple studies are in favor of the contribution of mid-chain HETEs to CH development. In this regard, mid-chain HETEs were found to be elevated following pressure overload-mediated CH (El-Sherbeni and El-Kadi 2014). As a CH model, the descending aortic constriction (DAC) is clinically invaluable as the development of CH takes longer time periods (Patten and Hall-Porter 2009). The formation of mid-chain HETEs was associated with increased CYP1B1 protein expression. The contribution of CYP1B1 to mid-chain HETEs production was ascertained via the recombinant CYP1B1 ability to generate mid-chain HETEs (Choudhary et al. 2004; El-Sherbeni and El-Kadi 2014). Similar to DAC model, our lab reported elevated mid-chain HETEs in Ang II-treated rats. Of note, rats pretreated with tetramethoxy stilbene (TMS), which is a specific inhibitor of CYP1B1, were protected from Ang II-mediated CH (Elkhatali et al. 2017). Critically, the cardioprotection against CH correlated with significant reduction in mid-chain HETE levels proposing a pivotal involvement of mid-chain HETEs in CH and also affirms that CYP1B1 is crucial in mid-chain HETEs formation.
Effects of quercetin on Aroclor 1254-induced expression of CYP450 and cytokines in pregnant rats
Published in Journal of Immunotoxicology, 2019
Lina Xu, Xiaojun Guo, Nan Li, Qing Pan, Yu Zhong Ma
CYP1A1 mRNA expression in control rat liver tissues was nominal (expression relative to that of CYC housekeeping gene = 0.02 [± 0.00]; Figure 2). CYP1B1 mRNA expression in these tissues were 0.41 [± 0.04]. Aroclor 1254 treatment alone induced significant 55.9- and 1.7-fold increases in, respectively, CYP1A1 (0.91 [± 0.08]) and CYP2B1 (0.71 [± 0.05]) expression. The lowest dose of quercetin again had no obvious impact on CYP1A1 (0.80 [± 0.07]) and CYP2B1 (0.72 [± 0.04]) relative (to CYC housekeeping gene) expression levels. However, a higher dose of quercetin (150 mg/kg) significantly blocked these inductions, with expression of each in the rat livers being decreased to now just 0.35- (CYP1A1; 0.60 [± 0.06]) and 0.27-fold (CYP2B1; 0.52 [± 0.03]) (each relative to CYC housekeeping gene). Values in the highest quercetin dose group (300 mg/kg) also indicated reduction in dam liver CYP1A1 (0.66 [± 0.04]) and CYP2B1 (0.62 [± 0.02]) expression levels. However, as these remained on par with the values in the Group D rats, this indicated no consistent quercitin dose-related effect. Interestingly, even with the mitigation, values of CYP1A1 expression in the Group D and E dams were still significantly higher than in the control rat liver samples.
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