Sex differences in constitutive mRNA levels of CYP2B22, CYP2C33, CYP2C49, CYP3A22, CYP3A29 and CYP3A46 in the pig liver: Comparison between Meishan and Landrace pigs

Kojima, Misaki; Degawa, Masakuni

doi:10.1016/j.dmpk.2016.02.001

Cited by 32 publications

(40 citation statements)

References 56 publications

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“…Based on these differences, CYP2A19 protein abundance could be breed-dependent, but data regarding its ontogeny remain scarce. Nevertheless, CYP2A19 sex-related differences with higher protein expression in female in comparison to male Göttingen Minipig, were in accordance with earlier studies (Rasmussen et al, 2011;Kojima and Degawa, 2016;Millecam et al, 2018). Sex-related differences in CYP abundance will be discussed later.…”

Section: General Aspectssupporting

confidence: 88%

Hepatic Cytochrome P450 Abundance and Activity in the Developing and Adult Göttingen Minipig: Pivotal Data for PBPK Modeling

et al. 2021

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The Göttingen Minipig is gaining ground as nonrodent species in safety testing of drugs for pediatric indications. Due to developmental changes in pharmacokinetics and pharmacodynamics, physiologically based pharmacokinetic (PBPK) models are built to better predict drug exposure in children and to aid species selection for nonclinical safety studies. These PBPK models require high quality physiological and ADME data such as protein abundance of drug metabolizing enzymes. These data are available for man and rat, but scarce for the Göttingen Minipig. The aim of this study was to assess hepatic cytochrome P450 (CYP) protein abundance in the developing Göttingen Minipig by using mass spectrometry. In addition, sex-related differences in CYP protein abundance and correlation of CYP enzyme activity with CYP protein abundance were assessed. The following age groups were included: gestational day (GD) 84–86 (n = 8), GD 108 (n = 6), postnatal day (PND) 1 (n = 8), PND 3 (n = 8), PND 7 (n = 8), PND 28 (n = 8) and adult (n = 8). Liver microsomes were extracted and protein abundance was compared to that in adult animals. Next, the CYP protein abundance was correlated to CYP enzyme activity in the same biological samples. In general, CYP protein abundance gradually increased during development. However, we observed a stable protein expression over time for CYP4A24 and CYP20A1 and for CYP51A1, a high protein expression during the fetal stages was followed by a decrease during the first month of life and an increase toward adulthood. Sex-related differences were observed for CYP4V2_2a and CYP20A1 at PND 1 with highest expression in females for both isoforms. In the adult samples, sex-related differences were detected for CYP1A1, CYP1A2, CYP2A19, CYP2E1_2, CYP3A22, CYP4V2_2a and CYP4V2_2b with higher values in female compared to male Göttingen Minipigs. The correlation analysis between CYP protein abundance and CYP enzyme activity showed that CYP3A22 protein abundance correlated clearly with the metabolism of midazolam at PND 7. These data are remarkably comparable to human data and provide a valuable step forward in the construction of a neonatal and juvenile Göttingen Minipig PBPK model.

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Section: General Aspectssupporting

confidence: 88%

Hepatic Cytochrome P450 Abundance and Activity in the Developing and Adult Göttingen Minipig: Pivotal Data for PBPK Modeling

et al. 2021

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“…In the liver of fattening LWDL pigs, the CYP2C18 , UGT17B1 , and CYP3A4 genes extracted to “retinol metabolism” (hsa00830) were upregulated. This observation is consistent with our previous results that those hepatic mRNA levels were higher in Landrace fattening pigs than in Meishan fattening pigs [ 36 , 37 ]. Furthermore, the gene coding for retinol dehydrogenase 16 (all-trans) (RDH16), an enzyme for retinol metabolism, was upregulated in the liver and fat of suckling and/or fattening LWDM pigs ( Table 4 ).…”

Section: Discussionsupporting

confidence: 94%

Differences in gene expression profiles for subcutaneous adipose, liver, and skeletal muscle tissues between Meishan and Landrace pigs with different backfat thicknesses

et al. 2018

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Backfat thickness is one of the most important traits of commercially raised pigs. Meishan pigs are renowned for having thicker backfat than Landrace pigs. To examine the genetic factors responsible for the differences, we first produced female crossbred pig lines by mating Landrace (L) × Large White (W) × Duroc (D) females (LWD) with Landrace (L) or Meishan (M) boars (i.e., LWD × L = LWDL for Landrace offspring and LWD × M = LWDM for the Meishan offspring). We confirmed that LWDM pigs indeed had a thicker backfat than LWDL pigs. Next, we performed gene expression microarray analysis in both genetic lines to examine differentially expressed genes (DEGs) in energy metabolism-related tissues, subcutaneous adipose (fat), liver, and longissimus dorsi muscle tissues. We analyzed the annotation of DEGs (2-fold cutoff) to functionally categorize them by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. The number of DEGs in muscle tissues of both lines was much less than that in fat and liver tissues, indicating that DEGs in muscle tissues may not contribute much to differences in backfat thickness. In contrast, several genes related to muscle (in fat tissue) and lipid metabolism (in liver tissue) were more upregulated in LWDM pigs than LWDL pigs, indicating that those DEGs might be responsible for differences in backfat thickness. The different genome-wide gene expression profiles in the fat, liver, and muscle tissues between genetic lines can provide useful information for pig breeders.

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“…The expression of CYP1A1 is correlated with carcinogen bioactivation ( Guengerich, 1988 ) and the biotransformation of various chemical substrates by oxygenation, demethylation, or dealkylation. The pig is a valuable animal model as a substitute for humans in pharmacological and toxicological studies ( Kojima and Degawa, 2016 ). Porcine CYP1A1 (pCYP1A1) is the orthologous protein to human CYP1A1, which plays a key role in the metabolism of various toxic and carcinogenic compounds ( Ma and Lu, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Sp1, Instead of AhR, Regulates the Basal Transcription of Porcine CYP1A1 at the Proximal Promoter

Xie

Jiang

et al. 2018

Front. Pharmacol.

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Pigs are commonly used as an animal model to evaluate the toxic effects of exogenous compounds. Cytochrome P450 1A1 (CYP1A1) metabolizes numerous exogenous compounds and is abundantly expressed in the liver, kidneys, and intestines. The high amino acid similarity between human and porcine CYP1A1 indicates that they probably have the same metabolic characteristics. Therefore, understanding the regulatory mechanism of CYP1A1 expression in pigs is particularly important for predicting the toxicology and metabolic kinetics of exogenous chemicals. Currently, the transcriptional regulation of porcine CYP1A1 has rarely been studied, especially regarding basal transcription. In this study, we first confirmed that the key regulatory elements of porcine CYP1A1 basal transactivation are in the proximal promoter region using promoter truncation analysis via a dual luciferase assay in a porcine kidney cell line LLC-PK1. Two overlapping cis-elements, the xenobiotic response element (XRE) and GC box, in this proximal region potentially play key roles in the basal transactivation of porcine CYP1A1. Furthermore, using electrophoretic mobility shift assay and chromatin immunoprecipitation, the GC box binding protein Sp1 was confirmed to bind to the proximal promoter of porcine CYP1A1, instead of AhR, the XRE binding protein. In LLC-PK1 cells, by knocking down either Sp1 or AhR, the expression of porcine CYP1A1 at the mRNA level and protein level was significantly downregulated, suggesting both proteins are important for porcine CYP1A1 expression. However, promoter activity analysis in LLC-PK1 cells treated with an AhR agonist and antagonist confirmed that AhR does not participate in the basal regulation of porcine CYP1A1 at the proximal promoter. In conclusion, our study revealed that the proximal promoter is the key regulatory region for porcine CYP1A1 basal expression. Although AhR plays an important role in the transactivation of porcine CYP1A1 expression, the key determinant transcription factor for its basal transactivation is Sp1 at the proximal promoter of porcine CYP1A1.

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Sex differences in constitutive mRNA levels of CYP2B22, CYP2C33, CYP2C49, CYP3A22, CYP3A29 and CYP3A46 in the pig liver: Comparison between Meishan and Landrace pigs

Cited by 32 publications

References 56 publications

Hepatic Cytochrome P450 Abundance and Activity in the Developing and Adult Göttingen Minipig: Pivotal Data for PBPK Modeling

Hepatic Cytochrome P450 Abundance and Activity in the Developing and Adult Göttingen Minipig: Pivotal Data for PBPK Modeling

Differences in gene expression profiles for subcutaneous adipose, liver, and skeletal muscle tissues between Meishan and Landrace pigs with different backfat thicknesses

Sp1, Instead of AhR, Regulates the Basal Transcription of Porcine CYP1A1 at the Proximal Promoter

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