Inhibition of Morphine Glucuronidation in the Liver Microsomes of Rats and Humans by Monoterpenoid Alcohols

Ishii, Yuji; Iida, Naoko; Miyauchi, Yuu; Mackenzie, Peter I.; Yamada, Hideyuki

doi:10.1248/bpb.b12-00568

Cited by 12 publications

(4 citation statements)

References 43 publications

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“…34,35 Additionally, a study in HLM indicated potential competitive inhibition of morphine metabolism via UGT2B7 and UGT1A3 by alcohol, but this was not through altering enzyme expression per se. 36 Our results did not demonstrate sex-related differences in the glucuronidation activity in HLMs using a large sample size in either adult or pediatric populations. The potential influence of ethnicity could not be assessed because most of the samples came from white donors.…”

Section: Discussioncontrasting

confidence: 66%

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Characterization of the Ontogeny of Hepatic UDP‐Glucuronosyltransferase Enzymes Based on Glucuronidation Activity Measured in Human Liver Microsomes

Badée

Qiu

Collier

et al. 2019

The Journal of Clinical Pharma

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An understanding of the postnatal development of hepatic UDP‐glucuronosyltransferase (UGT) enzymes is required for accurate prediction of the age‐dependent changes in pharmacokinetics of many drugs used in children. However, the maturation rate of hepatic UGT isoforms remains a major knowledge gap. This study aimed to establish the age‐associated changes in glucuronidation activity of 10 major hepatic UGT isoforms in humans, namely, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17. Human liver microsomes from pediatric and adult donors were incubated under optimized incubation conditions to assess the activity rates of hepatic UGT isoforms using a panel of 19 in vitro UGT probe substrates and clinically used drugs. Statistically strong correlations of glucuronidation activities allowed the ontogeny of UGT1A1, UGT1A4, UGT2B7, UGT2B10, and UGT2B15 to be established using multiple selective UGT substrates and matched human liver microsome samples. The postnatal development of hepatic UGTs is isoform‐dependent using either individual or cross‐correlated selective isoform substrates. Maximal adult activity was reached at different times ranging from within a month (UGT1A1, UGT2B4, UGT2B7, UGT2B10, and UGT2B15), during infancy (UGT1A3, UGT1A4, and UGT1A9), to adolescence (UGT1A6 and UGT2B17). This study provides an extensive characterization of the postnatal ontogeny profiles of hepatic UGT enzymes that are instrumental for predicting drug disposition via in vitro–in vivo extrapolation algorithms and verifying pharmacokinetic predictions against in vivo observations via pediatric physiologically based pharmacokinetic modeling in pediatric patients.

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Section: Discussioncontrasting

confidence: 66%

“…Alterations of nicotine glucuronidation via UGT2B10 and UGT2B17 was found to be ethnicity‐dependent . Additionally, a study in HLM indicated potential competitive inhibition of morphine metabolism via UGT2B7 and UGT1A3 by alcohol, but this was not through altering enzyme expression per se …”

Section: Discussionmentioning

confidence: 97%

Characterization of the Ontogeny of Hepatic UDP‐Glucuronosyltransferase Enzymes Based on Glucuronidation Activity Measured in Human Liver Microsomes

Badée

Qiu

Collier

et al. 2019

The Journal of Clinical Pharma

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“…When each UGT enzyme was individually assayed for inhibition, both menthol enantiomers exhibited high inhibition potential for UGT2B7-mediated formation of (S)-NNAL-O-Gluc. These data are similar to those from other studies in which menthol and other mercaptoid alcohols have been associated with the inhibition of UGT2B7 activity (Ishii et al, 2012). A similarly high inhibition potential was observed for UGT2B10-mediated formation of NNAL-N-Gluc.…”

Section: Discussionsupporting

confidence: 90%

Role of l- and d-Menthol in the Glucuronidation and Detoxification of the Major Lung Carcinogen, NNAL

et al. 2019

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Menthol, which creates mint flavor and scent, is often added to tobacco in both menthol and nonmenthol cigarettes. A potent tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is extensively metabolized to its equally carcinogenic metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) as (R)-or (S)-NNAL enantiomers. NNAL is detoxified by UDPglucuronosyltransferase (UGT) enzymes, with glucuronidation occurring on either NNAL's pyridine ring nitrogen (NNAL-N-Gluc) or the chiral alcohol [(R)-or (S)-NNAL-O-Gluc]. To characterize a potential effect by menthol on NNAL glucuronidation, in vitro menthol glucuronidation assays and menthol inhibition of NNAL-Gluc formation assays were performed. Additionally, NNAL and menthol glucuronides (MG) were measured in the urine of smokers (n 5 100) from the Southern Community Cohort Study. UGTs 1A9, 1A10, 2A1, 2A2, 2A3, 2B4, 2B7, and 2B17 all exhibited glucuronidating activity against both L-and D-menthol. In human liver microsomes, both L-and D-menthol inhibited the formation of each NNAL-Gluc, with a stereospecific difference observed between the formation of (R)-NNAL-O-Gluc and (S)-NNAL-O-Gluc in the presence of D-menthol but not L-menthol. With the exception of three nonmenthol cigarette smokers, urinary MG was detected in all menthol and nonmenthol smokers, with L-MG comprising >98% of total urinary MG. Levels of urinary NNAL-N-Gluc were significantly (P < 0.05) lower among subjects with high levels of total urinary MG; no significant changes in free NNAL were observed. These data suggest that the presence of menthol could lead to increases in alternative, activating metabolic pathways of NNAL in tobacco target tissues, increasing the opportunity for NNAL to damage DNA and lead to the development of tobacco-related cancers. SIGNIFICANCE STATEMENTHigh levels of the major menthol metabolite, menthol-glucuronide, was observed in the urine of smokers of either menthol or nonmenthol cigarettes. The fact that a significant inverse correlation was observed between the levels of urinary menthol-glucuronide and NNAL-Nglucuronide, a major detoxification metabolite of the tobacco carcinogen, NNK, suggests that menthol may inhibit clearance of this important tobacco carcinogen.

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“…The expressions of Ugt2B7, Ephx1, and glutathione S-transferase A2 (Gsta2) were downregulated 24 h post-injury compared to those of non-injured animals. In both rodents and humans, UGT2B7 is involved in the conjugation of many xenobiotics, including morphine (33). EPHX1 plays an important role in the activation and detoxification of exogenous chemicals (34); GSTA2 has glutathione peroxidase activity and protects cells from reactive oxygen species (35).…”

Section: Effect Of Tbi On Gene Expression In Liver Tissue and Plasma mentioning

confidence: 99%

Effect of Traumatic Brain Injury, Erythropoietin, and Anakinra on Hepatic Metabolizing Enzymes and Transporters in an Experimental Rat Model

Anderson

Peterson

Haar

et al. 2015

AAPS J

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In contrast to considerable data demonstrating a decrease in cytochrome P450 (CYP) activity in inflammation and infection, clinically, traumatic brain injury (TBI) results in an increase in CYP and UDP glucuronosyltransferase (UGT) activity. The objective of this study was to determine the effects of TBI alone and with treatment with erythropoietin (EPO) or anakinra on the gene expression of hepatic inflammatory proteins, drug-metabolizing enzymes, and transporters in a cortical contusion impact (CCI) injury model. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Plasma cytokine and liver protein concentrations of CYP2D4, CYP3A1, EPHX1, and UGT2B7 were determined. There was no effect of TBI, TBI + EPO, or TBI + anakinra on gene expression of the inflammatory factors shown to be associated with decreased expression of hepatic metabolic enzymes in models of infection and inflammation. IL-6 plasma concentrations were increased in TBI animals and decreased with EPO and anakinra treatment. There was no significant effect of TBI and/or anakinra on gene expression of enzymes or transporters known to be involved in drug disposition. TBI + EPO treatment decreased the gene expression of Cyp2d4 at 72 h with a corresponding decrease in CYP2D4 protein at 72 h and 7 days. CYP3A1 protein was decreased at 24 h. In conclusion, EPO treatment may result in a significant decrease in the metabolism of Cyp-metabolized drugs. In contrast to clinical TBI, there was not a significant effect of experimental TBI on CYP or UGT metabolic enzymes.

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Inhibition of Morphine Glucuronidation in the Liver Microsomes of Rats and Humans by Monoterpenoid Alcohols

Cited by 12 publications

References 43 publications

Characterization of the Ontogeny of Hepatic UDP‐Glucuronosyltransferase Enzymes Based on Glucuronidation Activity Measured in Human Liver Microsomes

Characterization of the Ontogeny of Hepatic UDP‐Glucuronosyltransferase Enzymes Based on Glucuronidation Activity Measured in Human Liver Microsomes

Role of l- and d-Menthol in the Glucuronidation and Detoxification of the Major Lung Carcinogen, NNAL

Effect of Traumatic Brain Injury, Erythropoietin, and Anakinra on Hepatic Metabolizing Enzymes and Transporters in an Experimental Rat Model

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