Sex-associated expression of mouse hepatic and renal CYP2B enzymes by glucocorticoid hormones

Jarukamjorn, Kanokwan; Sakuma, Tsutomu; Yamamoto, Makoto; Ôhara, Ayako; Nemoto, Nobuo

doi:10.1016/s0006-2952(01)00656-6

Cited by 27 publications

(4 citation statements)

References 49 publications

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“…A similar pattern of expression was observed for CYP1A2 and CYP2E1 in male rat liver [16]. Many Cyps and other genes active in drug metabolism show sex-differences in expression beginning at puberty [6,15,17-19]. Genes such as Cyp2b9, Cyp3a41 , and Cyp3a44 , are expressed at high levels in both male and female mouse liver prior to puberty, but are then selectively repressed in male liver, resulting in female-biased expression at adulthood [18-20].…”

Section: Introductionmentioning

confidence: 64%

Sex-specific mouse liver gene expression: genome-wide analysis of developmental changes from pre-pubertal period to young adulthood

Conforto

Waxman

2012

Biol sex dif

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BackgroundEarly liver development and the transcriptional transitions during hepatogenesis are well characterized. However, gene expression changes during the late postnatal/pre-pubertal to young adulthood period are less well understood, especially with regards to sex-specific gene expression.MethodsMicroarray analysis of male and female mouse liver was carried out at 3, 4, and 8 wk of age to elucidate developmental changes in gene expression from the late postnatal/pre-pubertal period to young adulthood.ResultsA large number of sex-biased and sex-independent genes showed significant changes during this developmental period. Notably, sex-independent genes involved in cell cycle, chromosome condensation, and DNA replication were down regulated from 3 wk to 8 wk, while genes associated with metal ion binding, ion transport and kinase activity were up regulated. A majority of genes showing sex differential expression in adult liver did not display sex differences prior to puberty, at which time extensive changes in sex-specific gene expression were seen, primarily in males. Thus, in male liver, 76% of male-specific genes were up regulated and 47% of female-specific genes were down regulated from 3 to 8 wk of age, whereas in female liver 67% of sex-specific genes showed no significant change in expression. In both sexes, genes up regulated from 3 to 8 wk were significantly enriched (p < E-76) in the set of genes positively regulated by the liver transcription factor HNF4α, as determined in a liver-specific HNF4α knockout mouse model, while genes down regulated during this developmental period showed significant enrichment (p < E-65) for negative regulation by HNF4α. Significant enrichment of the developmentally regulated genes in the set of genes subject to positive and negative regulation by pituitary hormone was also observed. Five sex-specific transcriptional regulators showed sex-specific expression at 4 wk (male-specific Ihh; female-specific Cdx4, Cux2, Tox, and Trim24) and may contribute to the developmental changes that lead to global acquisition of liver sex-specificity by 8 wk of age.ConclusionsOverall, the observed changes in gene expression during postnatal liver development reflect the deceleration of liver growth and the induction of specialized liver functions, with widespread changes in sex-specific gene expression primarily occurring in male liver.

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Section: Introductionmentioning

confidence: 64%

Sex-specific mouse liver gene expression: genome-wide analysis of developmental changes from pre-pubertal period to young adulthood

Conforto

Waxman

2012

Biol sex dif

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“…As a whole, present results are consistent with published data. Phenobarbital did not affect CYP2B gene expression in human and mouse kidney (Jarukamjorn et al, 2001;Kakizaki et al, 2003). Concerning the lung, rat and rabbit pulmonary CYP2Bs did not respond to PB, even though NR1I2 and NR1I3 were expressed in both species (Lee et al, 1998;Skarin et al, 1999;Chirulli et al, 2005); likewise, mouse pulmonary CYP2B gene and protein were not modulated by PB, but measurable amounts of NR1I3 mRNA were never detected in this species (Pustylnyak et al, 2009).…”

Section: Discussionmentioning

confidence: 95%

Constitutive expression and phenobarbital modulation of drug metabolizing enzymes and related nuclear receptors in cattle liver and extra-hepatic tissues

Zancanella¹,

Giantin²,

Lopparelli³

et al. 2012

Xenobiotica

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In humans and rodents, phenobarbital (PB) induces hepatic and extra-hepatic drug metabolizing enzymes (DMEs) through the activation of specific nuclear receptors (NRs).In contrast, few data about PB transcriptional effects in veterinary species are available.2. The constitutive expression and modulation of PB-responsive NR and DME genes, following an oral PB challenge, were investigated in cattle liver and extra-hepatic tissues (duodenum, kidney, lung, testis, adrenal and muscle).3. Likewise to humans and rodents, target genes were expressed to a lower extent compared to the liver with few exceptions. 4. Phenobarbital significantly affected hepatic CYP2B22, 2C31, 2C87, 3A and UDPglucuronosyltransferase 1A1-like, glutathione S-transferase A1-like and sulfotransferase 1A1-like (SULT1A1-like) mRNAs and apoprotein amounts; in extra-hepatic tissues, only duodenum showed a significant down-regulation of SULT1A1-like gene and apoprotein. Nuclear receptor mRNAs were never affected by PB. 5. Presented data are the first evidence about the constitutive expression of foremost DME and NR genes in cattle extra-hepatic tissues, and data obtained following a PB challenge are suggestive of species-differences in drug metabolism; altogether, these information are of value for the extrapolation of pharmacotoxicological data among species, the characterization of drug-drug interactions as well as the animal and consumer's risk caused by harmful residues formation.

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“…Corresponding WT controls (B6) were obtained from The Jackson Laboratory (Bar Harbor, ME) and used to produce the Cyp2b9/10/13-null mice. Cyp2b9, Cyp2b10, and Cyp2b13 are the three Cyp2b members primarily expressed in the liver (Cyp2b9/10/13) and found in tandem repeat (S1 Fig)[38–40]. Each of the three hepatic genes was targeted (Fig 1).…”

Section: Methodsmentioning

confidence: 99%

“…This mouse model lacks all of the Cyp2b members, but also lacks other Cyp2 members (2a4, 2a5, 2g1, 2s1) as well as five non-CYP genes found between the two Cyp clusters on chromosome 7 [38]. Our new mouse model lacks three of the five Cyp2b members, 2b9, 2b10, and 2b13, which are the primary hepatic Cyp2b’s found in tandem repeat [38–40]. There are six genes between the Cyp2b9/10/13 cluster and Cyp2b19 and Cyp2b23 (S1 Fig).…”

Section: Introductionmentioning

confidence: 99%

Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice

et al. 2017

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Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model. Compensatory changes in CYP expression that occur in these models may also occur in polymorphic humans, or may complicate interpretation of ADME studies performed using these models. The loss of CAR causes significant changes in several CYPs probably due to loss of CAR-mediated constitutive regulation of these CYPs. Expression and activity changes include significant repression of Cyp2a and Cyp2b members with corresponding drops in 6α- and 16β-testosterone hydroxylase activity. Further, the ratio of 6α-/15α-hydroxylase activity, a biomarker of sexual dimorphism in the liver, indicates masculinization of female CAR-null mice, suggesting a role for CAR in the regulation of sexually dimorphic liver CYP profiles. The loss of Cyp3a causes fewer changes than CAR. Nevertheless, there are compensatory changes including gender-specific increases in Cyp2a and Cyp2b. Cyp2a and Cyp2b were down-regulated in CAR-null mice, suggesting activation of CAR and potentially PXR following loss of the Cyp3a members. However, the loss of Cyp2b causes few changes in hepatic CYP transcript levels and almost no significant compensatory changes in protein expression or activity with the possible exception of 6α-hydroxylase activity. This lack of a compensatory response in the Cyp2b9/10/13-null mice is probably due to low CYP2B hepatic expression, especially in male mice. Overall, compensatory and regulatory CYP changes followed the order CAR-null > Cyp3a-null > Cyp2b-null mice.

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Sex-associated expression of mouse hepatic and renal CYP2B enzymes by glucocorticoid hormones

Cited by 27 publications

References 49 publications

Sex-specific mouse liver gene expression: genome-wide analysis of developmental changes from pre-pubertal period to young adulthood

Sex-specific mouse liver gene expression: genome-wide analysis of developmental changes from pre-pubertal period to young adulthood

Constitutive expression and phenobarbital modulation of drug metabolizing enzymes and related nuclear receptors in cattle liver and extra-hepatic tissues

Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice

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