This chapter is an update of the data on substrates, reactions, inducers, and inhibitors of human CYP enzymes published previously by Rendic and DiCarlo (1), now covering selection of the literature through 2001 in the reference section. The data are presented in a tabular form (Table 1) to provide a framework for predicting and interpreting the new P450 metabolic data. The data are formatted in an Excel format as most suitable for off-line searching and management of the Web-database. The data are presented as stated by the author(s) and in the case when several references are cited the data are presented according to the latest published information. The searchable database is available either as an Excel file (for information contact the author), or as a Web-searchable database (Human P450 Metabolism Database, www.gentest.com) enabling the readers easy and quick approach to the latest updates on human CYP metabolic reactions.

Summary of information on human cyp enzymes: human p450 metabolism data

Safety assessment of allylalkoxybenzene derivatives used as flavouring substances - methyl eugenol and estragole.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.20205

Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity

https://www.dangersalimentaires.com/wp-content/uploads/2011/04/FCT-5107-Furan.pdf

Application of the Margin of Exposure (MOE) approach to substances in food that are genotoxic and carcinogenic

Special Issue: Application of the Margin of Exposure (MoE) Approach to Substances in Food that are Genotoxic and Carcinogenic.

Cytochrome P450 mediated metabolism of methyleugenol to the proximate carcinogen 1'-hydroxymethyleugenol has been investigated in vitro. Kinetic studies undertaken in liver microsomes from control male Fischer 344 rats revealed that this reaction is catalyzed by high affinity (Km of 74.9 +/- 9.0 microM, Vmax of 1.42 +/- 0.17 nmol/min/nmol P450) and low affinity (apparent Km several mM) enzymic components. Studies undertaken at low substrate concentration (20 microM) with microsomes from livers of rats treated with the enzyme inducers phenobarbital, dexamethasone, isosafrole and isoniazid indicated that a number of cytochrome P450 isozymes can catalyze the high affinity component. In control rat liver microsomes, 1'-hydroxylation of methyleugenol (assayed at 20 microM substrate) was inhibited significantly (P < 0.05) by diallylsulfide (40%), p-nitrophenol (55%), tolbutamide (30%) and alpha-naphthoflavone (25%) but not by troleandomycin, furafylline, quinine or cimetidine. These results suggested that the reaction is catalyzed by CYP 2E1 and by another as yet unidentified isozyme(s) (most probably CYP 2C6), but not by CYP 3A, CYP 1A2, CYP 2D1 or CYP 2C11. Administration of methyleugenol (0-300 mg/kg/day for 5 days) to rats in vivo caused dose-dependent auto-induction of 1'-hydroxylation of methyleugenol in vitro which could be attributed to induction of various cytochrome P450 isozymes, including CYP 2B and CYP 1A2. Consequently, high dose rodent carcinogenicity studies are likely to over-estimate the risk to human health posed by methyleugenol. The rate of 1'-hydroxylation of methyleugenol in vitro in 13 human liver samples varied markedly (by 37-fold), with the highest activities being similar to the activity evident in control rat liver microsomes. This suggests that the risk posed by dietary ingestion of methyleugenol could vary markedly in the human population.

Cytochrome P450 mediated bioactivation of methyleugenol to 1'-hydroxymethyleugenol in Fischer 344 rat and human liver microsomes.

Methyleugenol is an allylbenzene food flavoring which has been shown to form DNA and protein adducts, and to cause hepatotoxicity and carcinogenicity in rodents. In order to investigate the nature of the protein adducts, specific antisera were raised by immunizing rabbits with conjugates prepared by coupling 1'-acetoxymethyleugenol, or its acidic congener 3,4-dimethoxycinnamic acid, to rabbit serum albumin (RSA). These polyclonal antisera were shown by enzyme linked immunosorbent assay (ELISA) to contain antibodies which recognized the 3,4-dimethoxyphenyl ring portion of methyleugenol. Analysis of livers from rats given methyleugenol i.p. for 5 days, at doses between 10 and 300 mg/kg/day, revealed dose-dependent formation of novel protein adducts which were recognized by the antisera. The adducts were detected by ELISA and by immunoblotting and were concentrated in the microsomal fraction, and were shown in inhibition studies to be derived from methyleugenol. A 44 kDa adduct was the only protein adduct detected in livers of rats given low loses of methyleugenol (10 or 30 mg/kg/day) and was the major adduct detected in rats given high doses of the compound (100 and 300 mg/kg/day). This adduct was solubilized when microsomal fractions were extracted using 0.1 M sodium carbonate, implying that it is a peripheral membrane protein. A pattern of protein adducts which mirrored the in vivo situation was generated when rat hepatocytes were incubated with 1'-hydroxymethyleugenol in vitro, but could not be reproduced in experiments undertaken using liver microsomes or postmitochondrial supernatants. These findings imply that generation of protein adducts in livers of rats given methyleugenol in vivo proceeds via the 1'-hydroxy metabolite and requires crucial cofactors, and/or structural features, which are present in intact hepatocytes but not in broken cell preparations and which remain to be defined.

Immunochemical detection of covalently modified protein adducts in livers of rats treated with methyleugenol.

https://doi.org/10.1016/j.isci.2022.105595

Serotonin-1A receptor, a psychiatric disease risk factor, influences offspring immunity via sex-dependent genetic nurture

DNA transposable elements and transposase-derived genes are present in most living organisms, including vertebrates, but their function is largely unknown. PiggyBac Transposable Element Derived 5 (PGBD5) is an evolutionarily conserved vertebrate DNA transposase-derived gene with retained nuclease activity in cells. Vertebrate brain development is known to be associated with prominent neuronal cell death and DNA breaks, but their causes and functions are not well understood. Here, we show that PGBD5 contributes to normal brain development in mice and humans, where its deficiency causes disorder of intellectual disability, movement and seizures. In mice, Pgbd5 is required for the developmental induction of post-mitotic DNA breaks and recurrent somatic genome rearrangements in neurons. Together, these studies nominate PGBD5 as the long-hypothesized neuronal DNA nuclease required for brain function in mammals. One-Sentence Summary PiggyBac Transposable Element Derived 5 (PGBD5) is required for brain development in humans and mice by promoting somatic neuronal genome rearrangements.

/pdf/a-transposase-derived-gene-required-for-human-brain-2a8q0ehy.pdf

P Bergin

Papers

Cytochrome P450 mediated bioactivation of methyleugenol to 1'-hydroxymethyleugenol in Fischer 344 rat and human liver microsomes.

Immunochemical detection of covalently modified protein adducts in livers of rats treated with methyleugenol.

Serotonin-1A receptor, a psychiatric disease risk factor, influences offspring immunity via sex-dependent genetic nurture

A transposase-derived gene required for human brain development