Roles of human liver cytochrome P450 3A4 and 1A2 enzymes in the oxidation of myristicin

Yun, Chul‐Ho; Lee, Hye Suk; Lee, Hee-Yong; Yim, Sung-Kun; Kim, Keon-Hee; Kim, Eun‐Hee; Yea, Sung-Su; Guengerich, F. Peter

doi:10.1016/s0378-4274(02)00397-1

Cited by 30 publications

(25 citation statements)

References 26 publications

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“…The latter species employs the 4-methoxybenzoate monooxygenase (O-demethylating, EC 1.14.99.15) for catalyzing this reaction [42]. In humans, the methylenedioxy group of a number of bioactive plant compounds or drugs such as safrol, myristicin, and stiripentol is cleaved [43][44][45]. Probably, this cleavage is catalyzed exclusively by human enzymes, which might also act on irilone, but not by the gut microbiota.…”

Section: Discussionmentioning

confidence: 99%

The red clover isoflavone irilone is largely resistant to degradation by the human gut microbiota

Braune

Maul

Schebb

et al. 2009

Mol. Nutr. Food Res.

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Intestinal bacteria may influence bioavailability and physiological activity of dietary isoflavones. We therefore investigated the ability of human intestinal microbiota to convert irilone and genistein in vitro. In contrast to genistein, irilone was largely resistant to transformation by fecal slurries of ten human subjects. The fecal microbiota converted genistein to dihydrogenistein, 6'-hydroxy-O-desmethylangolensin, and 2-(4-hydroxyphenyl)-propionic acid. However, considerable interindividual differences in the rate of genistein degradation and the pattern of metabolites formed from genistein were observed. Only one metabolite, namely dihydroirilone, was formed from irilone in minor amounts. In further experiments, Eubacterium ramulus, a prevalent flavonoid-degrading species of the human gut, was tested for transformation of irilone. In contrast to genistein, irilone was not converted by E. ramulus. Irilone only differs from genistein by a methylenedioxy group attached to the A-ring of the isoflavone skeleton. This substitution obviously restricts the degradability of irilone by human intestinal bacteria.

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Section: Discussionmentioning

confidence: 99%

The red clover isoflavone irilone is largely resistant to degradation by the human gut microbiota

Braune

Maul

Schebb

et al. 2009

Mol. Nutr. Food Res.

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“…If both CYP1A1 and CYP1B1 are absent, and these two enzymes are well-known metabolic activators of BaP, what enzyme might compensate and take their place when both CYP1 genes are missing? Various CYP2C (Meehan et al, 1988;Yun et al, 1992;Bauer et al, 1995) and CYP3A (Yun et al, 1992;Bauer et al, 1995;Sun et al, 1995;Koley et al, 1997;Fukuhara et al, 1999;James et al, 2005) enzymes, some of which are PAH-inducible, have been shown in various vertebrates to metabolize PAHs such as BaP. Interestingly, microarray data revealed by far the most striking increases in CYP3A59 mRNA upregulation, which peaked at 8 weeks of oral BaP; these data strongly suggest-but do not prove-that CYP3A59 is the most likely BaP-inducible candidate responsible for initiation of BaP-induced SCC (Gálvez-Peralta et al, 2013).…”

Section: Cyp1a1-mediated Detoxication Of Oral Benzo[a]pyrenementioning

confidence: 91%

Oral Benzo[a]pyrene: Understanding Pharmacokinetics, Detoxication, and Consequences—Cyp1Knockout Mouse Lines as a Paradigm

et al. 2013

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Benzo [a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH); this ubiquitous environmental carcinogenic agent is found in tobacco smoke, charcoal-grilled foods, and PAH-contaminated surfaces of roofs, playgrounds, and highways. Cytochrome P450 1 wild-type, Cyp1a2(2/2), Cyp1b1(2/2), or Cyp1a2/1b1(2/2) knockouts, and mice with Cyp1a1 expression deleted in hepatocytes can ingest large oral BaP doses (125 mg/kg/d) without apparent toxicity. Cyp1a1(2/2) and Cyp1a1/1a2(2/2) knockouts and mice with Cyp1a1 expression deleted in gastrointestinal (GI) tract epithelial cells develop immunotoxicity and die within 32 days, indicating that GI tract inducible CYP1A1 is absolutely required for detoxication of oral BaP. Cyp1a1/1b1(2/2) and Cyp1a1/1a2/1b1(2/2) mice are rescued from immunosuppression and early death due to absent metabolic activation of BaP by CYP1B1 in immune cells. Ten-fold lower oral BaP doses result in adenocarcinoma of the proximal small intestine (PSI) in Cyp1a1(2/2) mice; Cyp1a1/1b1(2/2) double-knockout mice show no PSI cancer but develop squamous cell carcinoma of the preputial gland duct (PGD). BaP-metabolizing CYP1B1 in the PSI and CYP3A59 in the PGD are the most likely candidates to participate in tumor initiation in the epithelial cells of these two tissues; oncogenes and tumor-suppressor genes upregulated and downregulated during tumorigenesis are completely different between these tissues. This "oral BaP Cyp1" mouse paradigm represents a powerful teaching tool, showing that gene-environment interactions depend on route-of-administration: the same oral, but not intraperitoneal, BaP exposure leads to dramatic differences in target-organ toxicity and tumor type as a function of dose and Cyp1 genotype.

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“…In addition, CYP2C9 metabolises endogenous substrates arachidonic and linolenic acid (105). CYP2C9 also mediates 3-hydroxylation of B[a]P and metabolic activation of several PAH-diols to active metabolites at much slower rates than those by CYP1 enzymes (106). Genetic polymorphisms of CYP2C9 include more than 34 alleles (41).…”

Section: Cyp2c9mentioning

confidence: 99%

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Božina¹,

Bradamante

Lovrić

2009

Archives of Industrial Hygiene and Toxicology

166

111

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The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.

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Roles of human liver cytochrome P450 3A4 and 1A2 enzymes in the oxidation of myristicin

Cited by 30 publications

References 26 publications

The red clover isoflavone irilone is largely resistant to degradation by the human gut microbiota

The red clover isoflavone irilone is largely resistant to degradation by the human gut microbiota

Oral Benzo[a]pyrene: Understanding Pharmacokinetics, Detoxication, and Consequences—Cyp1Knockout Mouse Lines as a Paradigm

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

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