Focused DNA microarray analysis for sex-dependent gene expression of drug metabolizing enzymes, transporters and nuclear receptors in rat livers and kidneys

Iwano, Shunsuke; Higashi, Eriko; Miyoshi, Takefumi; Ando, Akihiro; Miyamoto, Yohei

doi:10.2131/jts.37.863

Cited by 14 publications

(6 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To summarize, pharmacokinetics of gentiopicroside and swertiamarin in rats are subject to a gender effect, which could give rise to individual differences in drug efficacy and toxicity if it translates to human. It has been reported that the activity of most CYP enzymes are significantly lower in female rats than in male rats,[21,22] which may explain the gender difference in the pharmacokinetics of gentiopicroside and swertiamarin observed in this study. However, further studies are required to explore the mechanism of this gender effect to better understand the pharmacokinetic profiles of gentiopicroside and swertiamarin.…”

Section: Resultsmentioning

confidence: 53%

A rapid and sensitive UFLC-MS/MS method for the simultaneous determination of gentiopicroside and swertiamarin in rat plasma and its application in pharmacokinetics

Feng

Zhu

Guan

et al. 2014

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 53%

A rapid and sensitive UFLC-MS/MS method for the simultaneous determination of gentiopicroside and swertiamarin in rat plasma and its application in pharmacokinetics

Feng

Zhu

Guan

et al. 2014

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

show abstract

“…Sex differences in CYPs and UGTs expression levels were reported in animal models . Higher paracetamol glucuronide levels were reported in female than in male rats , and recently, higher ugt1a9 expression in females was reported in liver and kidney from different rat strains, suggesting that it is not a strain‐related observation . The observed dimorphic propofol glucuronidation metabolism might be involved in the therapeutic effect of propofol as a significant, prolonged anaesthetic effect that was observed in rodents with a mixture of propofol and glucuronide inhibitor compared to their littermate without glucuronide inhibitor .…”

Section: Discussionmentioning

confidence: 95%

Sex Difference in Formation of Propofol Metabolites: A Replication Study

Choong

Loryan

Lindqvist

et al. 2013

Basic Clin Pharma Tox

View full text Add to dashboard Cite

Women recover faster from propofol anaesthesia and have been described to have a higher incidence of awareness during surgery, compared to men -an effect that may be inherent in sex differences in propofol metabolism. In an observational study, 98 ASA I-II patients treated with continuous propofol infusion were recruited. The associations between sex and CYP2B6 and UGT1A9 polymorphisms with dose-and weight-adjusted area under the total plasma level time curves (AUC) for propofol, and its metabolites propofol glucuronide (PG), 4-hydroxypropofol (OHP) and hydroxyl glucuronide metabolites 4-hydroxypropofol-1-O-b-D-glucuronide (Q1G) and 4-hydroxypropofol-4-O-b-D-glucuronide (Q4G), were analysed. Significantly higher AUC of PG (1.3 times, p = 0.03), Q1G (2.9 times, p < 0.001), Q4G (2.4 times, p < 0.01) and OHP (4.6 times, p = 0.01) were found in women (n = 53) than in men (n = 45) after intravenous infusion of propofol using target-controlled infusion system. There was, however, no significant impact of gene polymorphisms on propofol biotransformation. The results, which are supported by a previous pilot study using a propofol bolus dose, suggest that, compared to men, more rapid propofol metabolism may occur in women -a factor that may contribute to the mentioned differences in the efficacy of propofol anaesthesia between male and female patients.Propofol (2,6-diisopropylphenol) has become a widely used intravenous sedative agent for induction and maintenance of anaesthesia due to its rapid onset, relatively short emergence time and favourable safety profile. However, extensive interindividual variability in pharmacokinetic and pharmacodynamic parameters has previously been reported [1][2][3]. The biotransformation of propofol is a multipathway process: UDP-glucuronosyltransferase 1A9 (UGT1A9) is the main enzyme that catalyses the glucuronidation of propofol to propofol glucuronide (PG) [4]. Cytochrome P-450 enzyme 2B6 (CYP2B6) and to a lesser extent CYP2C9 are responsible for the hydroxylation of propofol to its hydroxylated metabolites. The major hydroxylated metabolite 4-hydroxypropofol (OHP) is subsequently metabolized to 4-hydroxypropofol-1-O-b-Dglucuronide (Q1G) and 4-hydroxypropofol-4-O-b-D-glucuronide (Q4G) [5]. Up to 90% of propofol is eliminated via the urine in the form of its glucuronidated metabolites [5,6], suggesting a crucial role of UGTs in its clearance.Single-nucleotide polymorphisms (SNPs) in UGT1A9 and CYP2B6 might contribute to the inter-individual variability in the formation rate of propofol metabolites. Age, weight, height and lean body mass have also been reported to play a relevant role in propofol clearance [7][8][9][10]. Furthermore, growing evidence suggests that sex is an independent factor that influences the rate of recovery from general anaesthesia [11]. A faster recovery has been reported in women after the administration of inhaled agents [11] or intravenous propofol [12], and faster decrease plasma propofol levels were reported in women than in men [1]. Currently, it is...

show abstract

“…In humans, morphine is metabolized by isozymes in the uridine 5’-diphosphoglucuronosyltransferase (UGT) 1 and 2 subfamilies, with almost all preferentially synthesizing M3G over M6G (~45–55% and 15% of metabolized product, respectively; [64]). Importantly, sex differences in the expression of UGT1 and 2 subclasses of enzymes have been reported in humans [65] and rats [66]. Further, these enzymes metabolize, and are directly influenced by, steroid hormones [67].…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent influences of morphine and its metabolites on pain sensitivity in the rat

Doyle

Murphy

2018

Physiology & Behavior

View full text Add to dashboard Cite

Preclinical studies report that the effective dose for morphine is approximately 2-fold higher in females than males. Following systemic administration, morphine is metabolized via Phase II glucuronidation in the liver and brain into two active metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), each possessing distinct pharmacological profiles. M6G binds to μ opioid receptors and acts as a potent analgesic. In contrast, M3G binds to toll-like receptor 4 (TLR4), initiating a neuroinflammatory response that directly opposes the analgesic effects of morphine and M6G. M3G serum concentrations are 2-fold higher in females than males, however, sex-specific effects of morphine metabolites on analgesia and glial activation in vivo remain unknown. The present studies test the hypothesis that increased M3G, and subsequent TLR4-mediated activation of glia, is a primary mechanism driving the attenuated response to morphine in females. We demonstrate that intra-PAG M6G results in a greater analgesic response in females than morphine alone. M6G analgesia was reversed with co-administration of (-)-naloxone, but not (+)-naloxone, suggesting that this effect is μ opioid receptor mediated. In contrast, intra-PAG administration of M3G significantly attenuated the analgesic effects of systemic morphine in males only, increasing the 50% effective dose of morphine two-fold (5.0 vs 10.3mg/kg) and eliminating the previously observed sex difference. An increase in IL-1β, IL-6 and TNF was observed in females following intra-PAG morphine or M6G. In males, only IL-1β levels increased following morphine. Changes in cytokine levels following M3G were limited to TNF in females. Together, these data implicate sex differences in morphine metabolism, specifically M3G, as a contributing factor in the attenuated response to morphine observed in females.

show abstract

Focused DNA microarray analysis for sex-dependent gene expression of drug metabolizing enzymes, transporters and nuclear receptors in rat livers and kidneys

Cited by 14 publications

References 23 publications

A rapid and sensitive UFLC-MS/MS method for the simultaneous determination of gentiopicroside and swertiamarin in rat plasma and its application in pharmacokinetics

A rapid and sensitive UFLC-MS/MS method for the simultaneous determination of gentiopicroside and swertiamarin in rat plasma and its application in pharmacokinetics

Sex Difference in Formation of Propofol Metabolites: A Replication Study

Sex-dependent influences of morphine and its metabolites on pain sensitivity in the rat

Contact Info

Product

Resources

About