Tissue Distribution and Gender-Specific Protein Expression of Cytochrome P450 in five Mouse Genotypes with a Background of FVB

Chen, Jiamei M; Zhang, Qisong S; Li, Xiaoyan Y; Gong, Xia; Ruan, Yanjiao; Zeng, Shi; Lu, Linlin; Qi, Xiaoxiao; Wang, Ying; Hu, Ming; Zhu, Lijun; Liu, Zhongqiu Q

doi:10.1007/s11095-018-2389-2

Cited by 8 publications

(4 citation statements)

References 42 publications

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“…To characterise the in vivo toxicity of solasonine and to reveal the influence of genetic background on its toxicity, mice from four different strains, KM, ICR, C57BL/6, and BALB/c, were evaluated with Horn’s assays [33]. In order to exclude the influences of sex as shown in References [17,18], only male mice were used in this study. In addition, thanks to the extremely low absolute bioavailability of oral administration [34], mice were administered with solasonine by intraperitoneal injection.…”

Section: Resultsmentioning

confidence: 99%

“…We compared basal expression levels of the cyp450 family genes in the livers of mice from four strains, and revealed whether solasonine influenced cyp450 family gene expression. Four cyp450 family genes were basally expressed at a high level: cyp1a2, cyp2e1, cyp3a11, and cyp2d11; and three genes (i.e., cyp2d12, cyp2j12, and cyp4f37) were basally expressed at a low level in the livers of male C57BL/6 mice [18]. These genes were selected to be detected at the mRNA level by SYBR real-time PCR assay six days after the mice were treated by intraperitoneal injection with solasonine at a dose of 21.5 mg/kg, or with a vehicle.…”

Section: Resultsmentioning

confidence: 99%

“…For studies on drug biotransformation and function, cyp1a2, cyp2e1, and cyp3a11, which are expressed at high levels in human and murine livers, are often employed [9,17,18,19]. Of note, basal levels of the expression of genes in the cyp450 family were reported to be dependent on factors such as gender [17,18], diseases [20], stresses [21], or age [22]. Here, we hypothesise that genetic background is a non-ignorable factor that can modify the pharmacological and toxicological function of drugs by modulating the induced expression of cyp450 genes upon drug administration.…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Toxicity of Solasonine and Its Effects on cyp450 Family Gene Expression in the Livers of Male Mice from Four Strains

Zhong

Chen

et al. 2018

Toxins

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Solasonine was reported to inhibit tumour cell growth in several different models. The in vivo toxicity of solasonine, the effects of genetic background on its toxicity, and its possible roles in regulating the expression of cyp450 family genes were still unclear and required characterisation. Here, Horn’s assays were performed on male mice from four different strains, and the expression of cyp450 family genes in their livers was examined by RT-PCR and ELISA. Mice treated by intraperitoneal injection with high levels of solasonine showed immediate post-excitatory depression, intraperitoneal tissue adhesion, and dissolving of cells in the liver. Furthermore, these four mouse strains showed different toxicological sensitivity to solasonine. The strains, in decreasing order of LD50 value, rescuing speed of body weight, and more severe pathological symptoms, were KM, ICR, C57BL/6, and BALB/c. Interestingly, more cyp450 genes were downregulated at the mRNA and/or protein level in the livers of male mice from C57BL/6 or BALB/c strains than those from KM or ICR strains. These results suggest that (1) Solasonine has hepatic toxicity and downregulates cyp450 genes expression at transcriptional and/or post-transcriptional levels; (2) Genetic background is an important factor which can affect the in vivo toxicity; (3) Downregulation of cyp450 gene expression in the liver may be a clue to help understand whether or not a given strain is sensitive to solasonine; (4) Influences on the expression of cyp450 genes should be considered when using solasonine alone, or in combination with other drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In Vivo Toxicity of Solasonine and Its Effects on cyp450 Family Gene Expression in the Livers of Male Mice from Four Strains

Zhong

Chen

et al. 2018

Toxins

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“…It is well known that metabolic enzymes vary among species. CYP3A11, the isoenzyme of human CYP3A4 in mouse, which occupies the amount of 20% of CYPs, is mainly involved in the metabolism of endogenous and exogenous compounds ( Chen et al, 2018 ). The effect of DEX or KTZ on mice CYP3A11 was verified by Q-PCR and Western blot analysis.…”

Section: Resultsmentioning

confidence: 99%

The Modulatory Role of CYP3A4 in Dictamnine-Induced Hepatotoxicity

Jiang

Dong-sheng

et al. 2018

Front. Pharmacol.

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Dictamni Cortex (DC) has been reported to be associated with acute hepatitis in clinic and may lead to a selective sub-chronic hepatotoxicity in rats. Nevertheless, the potent toxic ingredient and the underlying mechanism remain unknown. Dictamnine (DTN), the main alkaloid from DC, possesses a furan ring which was suspected of being responsible for hepatotoxicity via metabolic activation primarily by CYP3A4. Herein, the present study aimed to evaluate the role of CYP3A4 in DTN-induced liver injury. The in vitro results showed that the EC50 values in primary human hepatocytes (PHH), L02, HepG2 and NIH3T3 cells were correlated with the CYP3A4 expression levels in corresponding cells. Furthermore, the toxicity was increased in CYP3A4-induced PHH by rifampicin, and CYP3A4 over-expressed (OE) HepG2 and L02 cells. Contrarily, the cytotoxicity was decreased in CYP3A4-inhibited PHH and CYP3A4 OE HepG2 and L02 cells inhibited by ketoconazole (KTZ). In addition, the hepatotoxicity of DTN in enzyme induction/inhibition mice was further investigated in the aspects of biochemistry, histopathology, and pharmacokinetics. Administration of DTN in combination with KTZ resulted in attenuated liver injury, including lower alanine transaminase and aspartate transaminase activities and greater AUC and Cmax of serum DTN, whereas, pretreatment with dexamethasone aggravated the injury. Collectively, our findings illustrated that DTN-induced hepatotoxicity correlated well with the expression of CYP3A4, namely inhibition of CYP3A4 alleviated the toxicity both in vitro and in vivo, and induction aggravated the toxicity effects.

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Hepatic PGC-1α is not essential for fasting-induced cytochrome p450 regulation in mouse liver

Thøgersen

Kristensen²,

Olsen³

et al. 2020

Biochemical Pharmacology

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Tissue Distribution and Gender-Specific Protein Expression of Cytochrome P450 in five Mouse Genotypes with a Background of FVB

Abstract: A comprehensive understanding of the distribution characteristics and gender-specific expression of Cyps in major metabolic organs of WT and ET knockout FVB mice should contribute to a better understanding of drug efficacy and toxicity, and drug-drug interactions.

Cited by 8 publications

References 42 publications

In Vivo Toxicity of Solasonine and Its Effects on cyp450 Family Gene Expression in the Livers of Male Mice from Four Strains

In Vivo Toxicity of Solasonine and Its Effects on cyp450 Family Gene Expression in the Livers of Male Mice from Four Strains

The Modulatory Role of CYP3A4 in Dictamnine-Induced Hepatotoxicity

Hepatic PGC-1α is not essential for fasting-induced cytochrome p450 regulation in mouse liver

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