Effects of Pregnancy, Age and Sex in the Metabolism of Styrene in Rat Liver in Relation to the Regulation of Cytochrome P450 Enzymes

Kishi, Reiko; Sata, Fumihiro; Katakura, Yoko; Wang, Rui-Sheng; Nakajima, Tamie

doi:10.1539/joh.47.49

Cited by 12 publications

(5 citation statements)

References 35 publications

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“…The excretion of MA enantiomers showed great difference with the previous study which reported that a small excess of R-MA in workers exposed to air containing styrene and almost racemic MA in orally styrene-dosed Wistar rats [10]. Some factors can influence the metabolism of styrene such as age, sex, pregnancy or drinking alcohol probably via the change of specific P450 isozyme composition or the total content of P450 [11,12]. Linhart et al [4] reported that the ratio of MA enantiomers depends on the stereoselectivity of the formation of MA via styrene oxide as well as on the stereoselectivity of its further oxidation to phenylglyoxylic acid.…”

Section: Assay Of Ma Enantiomers and Pga In Rat Urinecontrasting

confidence: 69%

Simultaneous determination of mandelic acid enantiomers and phenylglyoxylic acid in urine by high-performance liquid chromatography with precolumn derivatization

Wang¹,

Wang²,

Tang³

et al. 2006

Journal of Chromatography B

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Section: Assay Of Ma Enantiomers and Pga In Rat Urinecontrasting

confidence: 69%

Simultaneous determination of mandelic acid enantiomers and phenylglyoxylic acid in urine by high-performance liquid chromatography with precolumn derivatization

Wang¹,

Wang²,

Tang³

et al. 2006

Journal of Chromatography B

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“…The data are consistent with rat hepatic microsomal content described in a limited number of postnatal, prepubertal, and pubertal age groups and adults in the literature (Borlakoglu et al, 1993;Kishi et al, 2005). Postnatal changes in microsomal protein content in the rat suggest a need for similar investigations with human pediatric livers (Johnsrud et al, 2003;Johnson et al, 2006).…”

Section: Discussionsupporting

confidence: 86%

Evaluation of the Assumptions of an Ontogeny Model of Rat Hepatic Cytochrome P450 Activity

Alcorn¹,

Elbarbry²,

Allouh³

2007

Drug Metab Dispos

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ABSTRACT:We previously reported an ontogeny model of hepatic cytochrome P450 (P450) activity that predicts in vivo P450 elimination from in vitro intrinsic clearance. The purpose of this study was to conduct investigations into key assumptions of the P450 ontogeny model using the developing rat model system. We used two developmentally dissimilar enzymes, CYP2E1 and CYP1A2, and male rats (n ‫؍‬ 4) at age groups representing critical developmental stages. Total body and liver weights and hepatic microsomal protein contents were measured. Following high-performance liquid chromatography analysis, apparent K M and V max estimates were calculated using nonlinear regression analysis for CYP2E1-and CYP1A2-mediated chlorzoxazone 6-hydroxylation and methoxyresorufin O-dealkylation, and V max estimates for p-nitrophenol and phenacetin hydroxylations, respectively. Hepatic scaling factors and Intentional and inadvertent exposures (i.e., environmental contamination, breast milk) of the developing neonate to xenobiotics raises significant concerns over the potential risks posed to the exposed neonate. However, ethical impediments and limited toxicity data in human pediatric populations hinder the assessment of such risk. Furthermore, evidence for age-dependent differences in susceptibility to toxicity precludes a simple adult-to-neonate extrapolation of toxicity risk based upon toxicology studies in adult populations (Clark et al., 2004;Ginsberg et al., 2004b). A need exists, then, for predictive paradigms for risk assessment in human pediatric populations.Pharmacokinetic processes, particularly elimination mechanisms, often underlie these age-related differences in susceptibility to toxicity. Most elimination processes undergo significant ontogeny (Alcorn and McNamara, 2002a) and their maturation status in the developing neonate may determine toxicological outcomes following a xenobiotic exposure (Ginsberg et al., 2004a;Barton, 2005). Consequently, knowledge of a neonate's elimination capacity is critical for toxicological risk assessments. To address this issue, recent efforts to use available data on the ontogeny of xenobiotic elimination mechanisms in humans and animals have lead to models that allow predictions of xenobiotic elimination in the developing neonate (Alcorn and McNamara, 2002b;Brent, 2004;Barton, 2005;Jarabek et al., 2005;Bjorkman, 2006;Edginton et al., 2006;Johnson et al., 2006;Nong et al., 2006) These models are either based upon physiological data from pediatric patients and adults or upon developmental toxicological assessments in suitable animal systems. In the only validated model approach (Nong et al., 2006), the authors reported that a physiologically based pharmacokinetic model premised upon knowledge of ageand subject-specific human CYP2E1 protein content and known physiological variables can be used to evaluate interindividual variation in internal dosimetry estimates for toluene (CYP2E1 substrate) exposures in children and represents a feasible approach for risk assess-

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“…Finally, characterization of P450 activity in the pregnant rat is an important step towards better understanding of the appropriateness of the rat as a model for drug disposition and fetal safety of xenobiotics during human pregnancy. Several studies using coumarin, progesterone, dehydroepiandrosterone, aminopyrine, styrene, toluene, and trichloroethylene have indicated a general decrease in drug metabolism during pregnancy in the rat although no studies using probe substrates have been published [20,[36][37][38]. The results of this study clearly demonstrate that the effects of pregnancy on cytochrome P450 expression and activity are enzyme-specific and that there is no general "pregnancy effect".…”

Section: Discussionmentioning

confidence: 55%

Changes in maternal liver Cyp2c and Cyp2d expression and activity during rat pregnancy

Dickmann

Tay

Senn

et al. 2008

Biochemical Pharmacology

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During human pregnancy, CYP2C9, CYP2C19, and CYP2D6 activities are altered. The aim of the current study was to determine if this phenomenon can be replicated in the rat, and to evaluate the mechanisms that contribute to the changes in Cyp2c and Cyp2d activity during pregnancy. The intrinsic clearance of dextromethorphan O-demethylation, a measure of Cyp2d2 activity, was decreased 80% at both days 9 and 19 of gestation when compared to non-pregnant controls. The decreased intrinsic clearance was a result of both decreased V(max) and increased K(m)-values at both days of gestation. Quantitative RT-PCR revealed that transcripts of Cyp2d2 and Cyp2d4 were significantly decreased at day 19 of pregnancy (p<0.05) when compared to day 9 and non-pregnant controls. The decrease in Cyp2d mRNA levels correlated with a decrease in several nuclear receptor mRNA levels (RARalpha, RXRalpha, HNF1 and HNF3beta) but not with the mRNA levels of nuclear receptors usually associated with regulation of P450 enzymes (PXR, CAR and HNF4alpha). In contrast, Cyp2c12 and Cyp2c6 transcription and protein expression were not significantly altered during rat pregnancy although the intrinsic clearance of Cyp2c6 mediated diclofenac 4'-hydroxylation was increased 2-fold on day 19 of gestation when compared to non-pregnant controls. The increase in intrinsic clearance was due to a decrease in the K(m)-value for 4'-hydroxydiclofenac formation. These data show that pregnancy significantly alters the expression and activity of drug metabolizing enzymes in an enzyme and gestational stage specific manner. These changes are likely to have toxicological and therapeutic implications.

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Effects of Pregnancy, Age and Sex in the Metabolism of Styrene in Rat Liver in Relation to the Regulation of Cytochrome P450 Enzymes

Cited by 12 publications

References 35 publications

Simultaneous determination of mandelic acid enantiomers and phenylglyoxylic acid in urine by high-performance liquid chromatography with precolumn derivatization

Simultaneous determination of mandelic acid enantiomers and phenylglyoxylic acid in urine by high-performance liquid chromatography with precolumn derivatization

Evaluation of the Assumptions of an Ontogeny Model of Rat Hepatic Cytochrome P450 Activity

Changes in maternal liver Cyp2c and Cyp2d expression and activity during rat pregnancy

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