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Biotransformation of Monoterpenoids by Microorganisms, Insects, and Mammals
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
Yoshiaki Noma, Yoshinori Asakawa
1,8-Cineole (122) gave 2β-hydroxy-1,8-cineole (125a) by CYP450 human and rat liver microsome. Cytochrome P450 molecular species responsible for metabolism of 1,8-cineole (122) was determined to be CYP3A4 and CYP3A1/2 in human and rat, respectively. Kinetic analysis showed that Km and Vmax values for the oxidation of 1,8-cineole (122) by human and rat treated with pregnenolone-16α-carbonitrile recombinant CYP3A4 were determined to be 50 μM and 90.9 nmol/min/nmol P450, 20 μM and 11.5 nmol/min/nmol P450, and 90 μM and 47.6 nmol/min/nmol P450, respectively (Shindo et al., 2000).
Mammalian CYP2D Members A Comparison of Structure, Function, and Regulation
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Recently, a CYP2D6/3A4-double transgenic mouse model has been developed by Felmlee et al. (2008). Both age and sex have considerable effects on hepatic CYP3A4 protein expression in 3- to 8-week-old transgenic mice, whereas neither factor alters CYP2D6 content. Constitutive CYP2D6 expression results in two- to threefold higher dextromethorphan O-demethylase activity in transgenic CYP2D6/3A4 mouse liver microsomes compared with wild-type mice. In contrast, expression of CYP3A4 in transgenic mouse livers does not increase dextromethorphan N-demethylase and midazolam 1′-hydroxylase activities (Felmlee et al. 2008). Pretreatment with pregnenolone 16α-carbonitrile (PCN) and 1,4-bis-2-(3,5-dichloropyridyloxy)-benzene (TCPOBOP) increases CYP3A4 expression in double transgenic mice. Interestingly, induction of hepatic CYP3A4 is greater in females than age- and treatment-matched males. Consequently, the increase in midazolam 1′-hydroxylase activity is significantly higher in 8-week-old female mice than in corresponding males (eightfold vs. sixfold for PCN treatment and sixfold vs. fivefold for TCPOBOP). Furthermore, increases in testosterone 6β-hydroxylase activity after CYP3A induction are relatively lower compared with those in midazolam 1′-hydroxylation for age-, sex-, and treatment-matched mice. The difference in CYP3A4 expression and induction between male and female mice suggests that women may be more susceptible to CYP3A4-mediated drug–drug interactions, and the extent of drug–drug interactions could be substrate dependent.
Fetal and Neonatal Drug Biotransformation
Published in Sam Kacew, Drug Toxicity and Metabolism in Pediatrics, 1990
In preliminary investigations with testosterone as a probe substrate,111 we found that uninduced rat fetuses near term possessed hepatic enzymes for catalysis of significant rates of hydroxylation at the 15β, 6β, 16α, 16β, and 2β positions on the steroid molecule. Testosterone hydroxylation at the 6β, 16α, and 16β positions can be catalyzed by several P450 isozymes.44 However, hydroxylation at the 15β and 2β positions suggested a constitutive presence of one or more members of the III A family. In addition, treatment of dams with pregnenolone- 16α-carbonitrile, a potent inducer of IIIA1, resulted in marked increases in fetal hydroxylation at positions 15β, 6β, 16β, and 2β which is indicative of induction of P450IIIA1 in the fetus. In addition, PCN produced more than 30-fold increases at the 7α position, which suggested steroidal induction of IIA1 or closely related isozyme(s) in the fetal liver.
Comparison of the hepatic metabolism of triazolam in wild-type andCyp3a-knockout mice for understanding CYP3A-mediated metabolism inCYP3A-humanised mice in vivo
Published in Xenobiotica, 2019
Genki Minegishi, Yasuhiro Kazuki, Yuki Yamasaki, Fuka Okuya, Hidetaka Akita, Mitsuo Oshimura, Kaoru Kobayashi
Prior to studies using CYP3A-humanised mice, we investigated in vitro TRZ metabolism and in vivo TRZ pharmacokinetics using wild-type (WT) and Cyp3a-KO mice. It is important to clarify whether TRZ can be used as a CYP3A probe in mice as well as humans, because pharmacokinetic profiles of midazolam, a typical human CYP3A substrate, are closely similar between WT and Cyp3a-KO mice (van Waterschoot et al., 2008). In addition, CYP3A is highly induced by pregnane X receptor (PXR, NR1I2) agonists in humans and mice (Moore et al., 2000). Thus, we studied the effect of pregnenolone 16α-carbonitrile (PCN), a mouse PXR agonist (Matheny et al., 2004; Staudinger et al., 2001a,b), on the pharmacokinetics of TRZ in WT and Cyp3a-KO mice to clarify whether TRZ can be used as a CYP3A probe for evaluating CYP3A induction in mice. Finally, we verified whether TRZ is used as a CYP3A probe in CYP3A-humanised mice in vivo.
Comparison of the hepatic and thyroid gland effects of sodium phenobarbital and pregnenolone-16α-carbonitrile in wild-type and constitutive androstane receptor (CAR)/pregnane X receptor (PXR) knockout rats
Published in Xenobiotica, 2019
Corinne Haines, Lynsey R. Chatham, Audrey Vardy, Clifford R. Elcombe, John R. Foster, Brian G. Lake
Like CAR, the pregnane X receptor (PXR) is involved in the regulation of genes involved in xenobiotic metabolism, cell proliferation, apoptosis and intermediary metabolism (Omiecinski et al., 2011; Pondugula et al., 2016; Yoshinari et al., 2008) Some PXR activators, such as pregnenolone-16α-carbonitrile (PCN), have been shown to increase liver weight and to induce RDS in both rat and mouse liver (Lake et al., 1998; Staudinger et al., 2001). However, no MOA for rodent liver tumour formation by PXR activators has been established, owing to the lack of suitable dose-response data for liver tumour formation by a non-genotoxic PXR activator (Elcombe et al., 2014).
Critical evaluation of the human relevance of the mode of action for rodent liver tumor formation by activators of the constitutive androstane receptor (CAR)
Published in Critical Reviews in Toxicology, 2021
Tomoya Yamada, Samuel M. Cohen, Brian G. Lake
As described above, the CAR, PXR, and PPARα nuclear receptors are highly expressed in liver and are involved in xenobiotic and intermediary metabolism (Omiecinski et al. 2011a; Corton et al. 2014, 2018; Yoshinari 2019; Daujat-Chavanieu and Gerbal-Chaloin 2020). Many studies have demonstrated that both CAR and PPARα activators can stimulate RDS in mouse and rat hepatocytes (Lake 2009, 2018; Cohen 2010; Corton et al. 2014; Elcombe et al. 2014; Corton et al. 2018; Yamada 2018). However, whether PXR activators are also mitogenic agents in rodent liver is less clear and no MOA for rodent liver tumor formation by PXR activators has been established (Elcombe et al. 2014; Shizu and Yoshinari 2020). For example, pregnenolone-16α-carbonitrile (PCN), which is a known rodent PXR activator (Omiecinski et al. 2011a; Yoshinari 2019), has been shown to stimulate hepatocyte RDS in mouse and rat liver in some studies (Lake et al. 1998; Staudinger et al. 2001; Haines et al. 2018a, 2019), but not in other investigations (Thatcher and Caldwell 1994; Shizu et al. 2013, 2021). While PCN has been reported to increase hepatocyte RDS in wild-type mice and rats in some studies, no such effects were observed in PXR KO mice and in both PXR KO and CAR KO/PXR KO rats; although a small increase was observed in PXR KO rats which may be due to crosstalk between the CAR and PXR receptors (Staudinger et al. 2001; Haines et al. 2018a, 2019). It has been suggested that PXR activation alone in either mouse or rat liver does not result in increased RDS, but rather that PXR activation augments RDS produced by other agents including both CAR and PPARα activators (Shizu et al. 2013; Yoshinari 2019). PCN did not promote mouse liver tumor formation after initiation with DEN, whereas PB produced the expected promotion of liver tumor formation; with the coadministration of PB and PCN not resulting in any enhancement of liver tumor formation over that observed with PB alone (Shizu et al. 2021). Overall, the available data suggest that PXR activation by itself does not result in rodent liver tumor formation.