Changes in the Gene Expression and Enzyme Activity of Hepatic Cytochrome P450 in Juvenile Sprague-Dawley Rats

Abstract

ABSTRACT. The developmental changes in the hepatic cytochrome P450 (CYP) content, mRNA expression of 12 hepatic CYP subtypes, and the enzyme activities of 5 hepatic CYP subfamilies in rats were investigated using non-treated male and female Sprague-Dawley rats of ages postnatal day (PD) 4, 16, 30 and 8 and 12 weeks. The hepatic proliferation kinetics was also determined by using the phospho-histone H3 (p-histon)-labeled hepatocyte index. The developmental changes in the enzyme activities of hepatic expression of CYP1A and CYP3A in rats were similar to those in humans, although there is no fetal-neonatal dominant CYP3A subtype in rat livers unlike human CYP3A7. On the other hand, the developmental pattern of expression of the CYP2C subfamily differed between humans and rats. Enzyme activity and mRNA expression of each hepatic CYP subtype in rats on PD 30 was similar to that after 8 weeks of age, except in the case of sex-dependent CYP subtypes. The p-histon-labeled hepatocyte index was approximately 10-fold higher in PD 30 rats than in 8-week-old rats. Therefore, the livers of juvenile rats, which have high hepatocellular proliferation activity and a sufficient amount of metabolic enzymes such as CYP, may be more sensitive to the cytotoxic and carcinogenic effects of chemicals than the livers of adult rats. Thus, our results on developmental difference of hepatic CYPs in juvenile rats are useful to identify underlying age-dependent susceptibility of chemical-induced toxicity, and to understand developmental change of chemical disposition.KEY WORDS: CYP subtype expression, cytochrome P450 (CYP) activity, juvenile rat, liver, phospho-histone H3-labeled hepatocyte.J. Vet. Med. Sci. 72(4): 471-479, 2010 Medicinal products intended for pediatric patients require special risk/benefit assessment, where the possible effects of the product on the subsequent developmental processes are also taken into consideration. Evidence for age-dependent differences in susceptibility to toxicity precludes a simple adult-to-child extrapolation of the toxicity risk determined by toxicological studies in adult populations [6,12]. Nonclinical studies using juvenile animals aim to obtain information on the potential difference in safety profiles between children and adults, which will support the development of pediatric medicines.Cytochrome P450 (CYP) mediates the rate-limiting step in xenobiotic elimination or bioactivation, and its rate of production and pattern of maturation change in an agedependent manner [14,15]. There are a lot of reports concerned with enzyme activities and expressions of CYP in the livers of adult and elder rats; especially, these reports indicates the existence and aging change of sex-specific and sex-dominant CYP subtypes, such as CYP2A2, CYP2C11, CYP2C12 and CYP3A2 [16,17,26]. These gender differences of hepatic CYP expression are regulated by growth hormone and sex hormones, and closely connected with not only the gender differences but also the specie differences in hepatic drug metabolisms and chemical-...

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

“…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.…”

Impact of age on hepatic cytochrome P450 of domestic male Camborough‐29 pigs

“…This phenomenon has been reported in all food‐producing animals such as sheep (Kaddouri et al ., ; Flåøyen & Jensen, ; Galtier & Alvinerie, ; Pretheeban et al ., ), cattle (Kawalek & el Said, ), and chicken (Hamilton & Bloom, ; Hamilton et al ., ; Lorr & Bloom, ; Lorr et al ., ; Hu, ). The typical pattern of CYP450 contents and activities for nonselective or overall CYP450 are low at neonates, increase to adults, and decrease to elders in mammals (Tanaka, ; Lupp et al ., ; Asaoka et al ., ). In commercial pork production, the growth phase from neonate to market body weight pigs is of the greatest practical significance, as the vast majority of pigs are raised only until approximately 5 months of age.…”

Metabolism of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) atropisomers in tissue slices from phenobarbital or dexamethasone-induced rats is sex-dependent

“…Briefly, earlier reports demonstrate that CYP2B1/2 and CYP3A2 expression and activities are lower in female rats, whereas no sex specific differences are observed for CYP1A2 (Asaoka et al, 2010). Furthermore, treatment with PB results primarily in an induction of CYP2B1 on both male and female rats (Waxman et al, 1985; Lee et al, 1992; Nims et al., 1993), whereas treatment with DEX induces CYP3A2 and CYP2B1 (Choudhuri et al, 1995; Meredith et al, 2003).…”

“…Studies with rat CYP2B1 and human CYP2B6 enzymes (Warner et al, 2009) and hepatic microsomes (Wu et al, 2011) demonstrate that chiral PCBs are enantioselectively metabolized to OH-PCBs by P450 enzymes. Expression and activity of CYP2B1 displays sex specific differences (Asaoka et al, 2010) and is inducible by a range of xenobiotics (Waxman and Walsh, 1982; Meredith et al, 2003). Similarly, the human orthologue, CYP2B6, is a highly inducible enzyme that may display sex specific differences in expression and activities (Zanger et al., 2007).…”