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Metabolism and Toxicity of Occupational Neurotoxicants: Genetic, Physiological, and Environmental Determinants
Published in Lucio G. Costa, Luigi Manzo, Occupatinal Neurotoxicology, 2020
Stefano M. Candura, Luigi Manzo, Anna F. Castoldi, Lucio G. Costa
The best characterized P450 polymorphism is that of cytochrome CYP2D6 (debrisoquine 4-hydroxylase). Its discovery followed the observation of unusual subject sensitivity to the hypotensive effect of debrisoquine,43 and of unusual neurological side effects in some patients treated with sparteine.44 It was subsequently clarified that the debrisoquine-sparteine polymorphism is caused by mutations of the CYP2D6 gene, which is part of a gene cluster on chromosome 22.45 Enzymatic activity is deficient in 7–10% of Caucasian subjects, who therefore show a slower oxidative metabolism.46,47 The frequency of poor metabolizers appears to be markedly lower in non-Caucasian populations.38 Since many therapeutic agents are oxidized by CYP2D6, the polymorphism has important clinical consequences, particularly in the use of cardiovascular and psychoactive drugs.8 With regard to neurotoxicology, CYP2D6 detoxifies 1,2,3,4-tetrahydroisoquinoline (TIQ) and MPTP. MPTP and other environmental neurotoxins with similar chemical structures have been implicated in the pathogenesis of Parkinson’s disease. Some researchers characterized the genotype that regulates 2D6 expression in Parkinson patients, suggesting that slow metabolizers have a two-three fold increased disease susceptibility.48,49
Pharmaceuticals: Some General Aspects
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The efficacy of a drug (as well as its toxicity) depends among others on the cytochrome P450 mediated drug metabolism (oxidative drug metabolizing enzymes; see also other chapters in Pharmaceutical Biocatalysis volumes). Of the more than 50 CYP450 enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 enzymes metabolize 90% of drugs, and of these P450 2D6 is responsible for the metabolism of almost 25% of drugs among them different types of analgesics, anti-arrhythmic agents, antidepressant and β-blockers. The response to standard doses of a drug may be different from patient to patient due to the fact that CYP 450 enzymes exhibit genetic variability (polymorphism). Those with two copies of wild-type genetic alleles are normal so-called “extensive” metabolizers whereas persons with two copies of variant alleles are “poor” metabolizers, and those with one variant and one wild-type allele show reduced enzyme activity (Lynch and Price, 2007). Flockhart (2007) provided a table with lists of drugs in columns under the designation of specific cytochrome P450 isoforms with published evidence (see cited literature) that the respective drug is metabolized, at least in part, via that isoform. In 2007 the FDA approved the first genotype test (Roche AmpliChip cytochrome P450 genotyping test) a DNA microarray that enables the detection of 29 polymorphisms of CYP2D6 and two of CYP2C19 from a blood sample. Investigations into cytochrome P450 2D6 genotype assessment and phenotype prediction using the Roche test have been reported by Rebsamen et al. (2009).
Risk assessment via genotoxicity, metabolism, apoptosis, and cell growth effects in a HepG2/C3A cell line upon treatment with Rubus rosifolius (Rosaceae) leaves extract
Published in Journal of Toxicology and Environmental Health, Part A, 2020
Ana Paula Oliveira De Quadros, Laíza Moura Almeida, Marcel Petreanu, Rivaldo Niero, Paulo Cesar Pires Rosa, Alexandra Christinie Helena Frankland Sawaya, Mario Sergio Mantovani, Isabel O’Neill De Mascarenhas Gaivão, Edson Luis Maistro
Another gene that exhibited enhanced relative expression was CYP3A4. This gene together with the CYP2D6 gene is responsible for the biotransformation of 70–80% of all medicines for clinical use (Zanger and Schwab 2013). Thus, the metabolism of R. rosifolius leaf extract, indicated by the increased expression of the CYP3A4 gene, may have resulted in the formation of genotoxic by-products, evidenced by the positive genotoxicity findings in the comet assay. This postulation is supported by the fact that most genotoxic compounds are active only after metabolism by liver enzymes (Cooper and Porter 2000). On the other hand, a significant decrease was detected in the expression of the CYP1A2 and CYP2C19 genes. This fall is interesting because previously Xu, Li, and Kong (2005) reported the induction of the expression of genes related to drug and xenobiotics metabolism is expected in the cells and/or organisms exposed to exogenous compounds. Data indicate that this pathway of metabolism needs to be better investigated in cells exposed to the extract of leaves of R. rosifolius.
Characterization of cytochrome P450s (CYP)-overexpressing HepG2 cells for assessing drug and chemical-induced liver toxicity
Published in Journal of Environmental Science and Health, Part C, 2021
Si Chen, Qiangen Wu, Xilin Li, Dongying Li, Nan Mei, Baitang Ning, Montserrat Puig, Zhen Ren, William H. Tolleson, Lei Guo
The choice of a cell model strongly depends on the research goals. Primary human hepatocytes are the most widely accepted cell model for pharmacological and toxicological studies, taking metabolic capability into account. The HepaRG cell line has recently emerged as a surrogate for primary human hepatocytes. Hepatic cell lines have been used for years; however, they are not the best representative of human liver cells due to the lack of metabolizing enzymes. To overcome it, we incorporated CYP metabolic capability in HepG2 cells by transducing lentiviral cDNA expression vectors containing the individual CYP sequences.42 Unlike the parental HepG2 cells that exhibit limited drug metabolic capacity,23,60 our cell lines express 14 CYPs individually at the transcriptional, translational, and functional levels (Table 1). To understand better the suitability of CYP-overexpressing HepG2 cell lines and provide a reference profile, comparisons were made among these three types of cells. HepaRG cells did not fully recapitulate the enzyme profile of primary human hepatocytes (Table 2). In particular, CYP2D6 was not detected in HepaRG cells, although that was expected since the donor for HepaRG cells was a poor CYP2D6 metabolizer.61,62 CYP2D6 has an important role in drug metabolism because it is the primary enzyme to metabolize 15-25% of clinically used drugs, including antiarrhythmics, antipsychotics, β-blockers, and anti-cancer drugs.54 The lack of CYP2D6 in HepaRG cell line limits its use for certain pharmacological and toxicological studies involving CYP2D6 activity.55