Non-P450 Drug-Metabolizing Enzymes: Contribution to Drug Disposition, Toxicity, and Development

Fukami, Tatsuki; Yokoi, Tsuyoshi; Nakajima, Miki

doi:10.1146/annurev-pharmtox-052220-105907

Cited by 33 publications

(23 citation statements)

References 122 publications

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“…However, the FMO-dependent S -oxidation of MTZ and ETU were significantly reduced in PB-treated cattle. A number of representative FMO substrates have been identified [ 159 ], and some of them have also been proved to be competitive inhibitors of these monooxygenases, thus leading to a decreased FMO catalytic activity. Methimazole is one of these [ 152 , 160 ].…”

Section: Discussionmentioning

confidence: 99%

Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization

Cantiello

Carletti

Giantin

et al. 2022

IJMS

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In cattle, phenobarbital (PB) upregulates target drug-metabolizing enzyme (DME) mRNA levels. However, few data about PB’s post-transcriptional effects are actually available. This work provides the first, and an almost complete, characterization of PB-dependent changes in DME catalytic activities in bovine liver using common probe substrates and confirmatory immunoblotting investigations. As expected, PB increased the total cytochrome P450 (CYP) content and the extent of metyrapone binding; moreover, an augmentation of protein amounts and related enzyme activities was observed for known PB targets such as CYP2B, 2C, and 3A, but also CYP2E1. However, contradictory results were obtained for CYP1A, while a decreased catalytic activity was observed for flavin-containing monooxygenases 1 and 3. The barbiturate had no effect on the chosen hydrolytic and conjugative DMEs. For the first time, we also measured the 26S proteasome activity, and the increase observed in PB-treated cattle would suggest this post-translational event might contribute to cattle DME regulation. Overall, this study increased the knowledge of cattle hepatic drug metabolism, and further confirmed the presence of species differences in DME expression and activity between cattle, humans, and rodents. This reinforced the need for an extensive characterization and understanding of comparative molecular mechanisms involved in expression, regulation, and function of DMEs.

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Section: Discussionmentioning

confidence: 99%

Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization

Cantiello

Carletti

Giantin

et al. 2022

IJMS

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“…However, they are not fully aware of what lies at the basis of such recommendations. The basic mechanism relies on the impact of polyphenols on the activity of drug-metabolizing enzymes, such as phase I and phase II enzymes, e.g., cytochrome P450, glutathione S-transferase, UDP-glucuronosyltransferase, sulfotransferase, N-acetyltransferase, methyltransferase, epoxide hydrolase, and NAD(P)H:quinone oxidoreductase [ 109 , 275 , 276 , 277 , 278 , 279 , 280 , 281 , 282 ].…”

Section: Interactions Of Polyphenolic Compounds With Drug Disposition...mentioning

confidence: 99%

Possible Side Effects of Polyphenols and Their Interactions with Medicines

Duda-Chodak

Tarko

2023

Molecules

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Polyphenols are an important component of plant-derived food with a wide spectrum of beneficial effects on human health. For many years, they have aroused great interest, especially due to their antioxidant properties, which are used in the prevention and treatment of many diseases. Unfortunately, as with any chemical substance, depending on the conditions, dose, and interactions with the environment, it is possible for polyphenols to also exert harmful effects. This review presents a comprehensive current state of the knowledge on the negative impact of polyphenols on human health, describing the possible side effects of polyphenol intake, especially in the form of supplements. The review begins with a brief overview of the physiological role of polyphenols and their potential use in disease prevention, followed by the harmful effects of polyphenols which are exerted in particular situations. The individual chapters discuss the consequences of polyphenols’ ability to block iron uptake, which in some subpopulations can be harmful, as well as the possible inhibition of digestive enzymes, inhibition of intestinal microbiota, interactions of polyphenolic compounds with drugs, and impact on hormonal balance. Finally, the prooxidative activity of polyphenols as well as their mutagenic, carcinogenic, and genotoxic effects are presented. According to the authors, there is a need to raise public awareness about the possible side effects of polyphenols supplementation, especially in the case of vulnerable subpopulations.

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“…Several hydrolases are involved in drug metabolism, viz. carboxylesterase (CES) 1, CES2, and arylacetamide deacetylase (AADAC), and have been well characterized (Fukami et al, 2022). CES1 tends to target compounds with relatively large acyl groups, whereas CES2 and AADAC tend to target compounds with relatively small acyl groups (Fukami et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Enzymes Involved in Nintedanib Metabolism in Humans

et al. 2023

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Nintedanib, which is used to treat idiopathic pulmonary fibrosis and non-small cell lung cancer, is metabolized to a pharmacologically inactive carboxylate derivative, BIBF1202, via hydrolysis and subsequently by glucuronidation to BIBF1202 acyl-glucuronide (BIBF1202-G). Since BIBF1202-G contains an ester bond, it can be hydrolytically cleaved to BIBF1202.In this study, we sought to characterize these metabolic reactions in the human liver and intestine. Nintedanib hydrolysis was detected in human liver microsomes (HLM) (CLint: 102.8 ± 18.9 µL/min/mg protein) but not in small intestinal preparations. CES1 was suggested to be responsible for nintedanib hydrolysis according to experiments using recombinant hydrolases and hydrolase inhibitors as well as proteomic correlation analysis using 25 individual HLM.BIBF1202 glucuronidation in HLM (3.6 ± 0.3 µL/min/mg protein) was higher than that in human intestinal microsomes (1.5 ± 0.06 µL/min/mg protein). UGT1A1 and gastrointestinal UGT1A7, UGT1A8, and UGT1A10 were able to mediate BIBF1202 glucuronidation. The impact of UGT1A1 on glucuronidation was supported by the finding that liver microsomes from subjects homozygous for the UGT1A1*28 allele showed significantly lower activity than those from subjects carrying the wild-type UGT1A1 allele. Interestingly, BIBF1202-G was converted to BIBF1202 in HLS9 at 70-fold higher rates than the rates of BIBF1202glucuronidation. An inhibition study and proteomic correlation analysis suggested that βglucuronidase is responsible for hepatic BIBF1202-G deglucuronidation. In conclusion, the major metabolic reactions of nintedanib in the human liver and intestine were quantitatively and thoroughly elucidated. This information could be helpful to understand the inter-and intraindividual variability in the efficacy of nintedanib.

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Non-P450 Drug-Metabolizing Enzymes: Contribution to Drug Disposition, Toxicity, and Development

Cited by 33 publications

References 122 publications

Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization

Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization

Possible Side Effects of Polyphenols and Their Interactions with Medicines

Characterization of Enzymes Involved in Nintedanib Metabolism in Humans

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