A Novel Female-Specific Member of the CYP3A Gene Subfamily in the Mouse Liver

Sakuma, Tsutomu; Takai, M; Endo, Yusuke; Kuroiwa, Masami; Ôhara, Ayako; Jarukamjorn, Kanokwan; Honma, Rieko; Nemoto, Nobuo

doi:10.1006/abbi.2000.1747

Cited by 72 publications

(73 citation statements)

References 29 publications

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“…5C), whereas the mean adult levels were similar. Cyp3A11 expression rose as expected in adult mice (43,45) but did not differ between the WT and KO mice at 3 weeks or in adulthood. Cyp1a2 levels were constant regardless of age or Mrp4 status (Fig.…”

Section: Lower Serum Testosterone In Young Mrp4supporting

confidence: 74%

Deregulated Hepatic Metabolism Exacerbates Impaired Testosterone Production in Mrp4-deficient Mice

Morgan

Cheepala

Wang

et al. 2012

Journal of Biological Chemistry

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Background:The role of the ABC transporter, Mrp4, in regulating Leydig cell testosterone synthesis is unknown. Results: In a murine genetic model the absence of Mrp4 impairs testosterone production by disrupting cAMP signaling. Conclusion: Mrp4 absence disrupts Leydig cell cAMP homeostasis by impairing luteinizing hormone-activated testosterone production. Significance: These findings reveal a mechanism for unexplained side effects of altered androgen production by therapeutics disrupting Mrp4 function.

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Section: Lower Serum Testosterone In Young Mrp4supporting

confidence: 74%

Deregulated Hepatic Metabolism Exacerbates Impaired Testosterone Production in Mrp4-deficient Mice

Morgan

Cheepala

Wang

et al. 2012

Journal of Biological Chemistry

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“…Indeed, in general studies have shown that CYP3A activity is higher in women than in men [201] . In line with the observation that estradiol and testosterone regulate the expression of CYP3A isoforms in the liver [209] , Parkinson et al [210] and Wang et al [204] demonstrated that women metabolize some CYP3A4 and CYP3A9 substrates faster than men do. It is known that vitamin E levels change under metabolic challenges, such as age-associated diseases or oxidative stress (see the section "Life-style and age influence the bioavailability of vitamin E" in the chapter on the bioavailability of vitamin E).…”

Section: Gender-specific Bioavailability Of Vitamin Ementioning

confidence: 75%

Complexity of vitamin E metabolism

Schmölz¹,

Birringer²,

Lorkowski³

et al. 2016

WJBC

176

138

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Bioavailability of vitamin E is influenced by several factors, most are highlighted in this review. While gender, age and genetic constitution influence vitamin E bioavailability but cannot be modified, life-style and intake of vitamin E can be. Numerous factors must be taken into account however, i.e. , when vitamin E is orally administrated, the food matrix may contain competing nutrients. The complex metabolic processes comprise intestinal absorption, vascular transport, hepatic sorting by intracellular binding proteins, such as the significant α-tocopherol-transfer protein, and hepatic metabolism. The coordinated changes involved in the hepatic metabolism of vitamin E provide an effective physiological pathway to protect tissues against the excessive accumulation of, in particular, non-α-tocopherol forms. Metabolism of vitamin E begins with one cycle of CYP4F2/CYP3A4-dependent ω-hydroxylation followed by five cycles of subsequent β-oxidation, and forms the water-soluble end-product carboxyethylhydroxychroman. All known hepatic metabolites can be conjugated and are excreted, depending on the length of their sidechain, either via urine or feces. The physiological handling of vitamin E underlies kinetics which vary between the different vitamin E forms. Here, saturation of the side-chain and also substitution of the chromanol ring system are important. Most of the metabolic reactions and processes that are involved with vitamin E are also shared by other fat soluble vitamins. Influencing interactions with other nutrients such as vitamin K or pharmaceuticals are also covered by this review. All these processes modulate the formation of vitamin E metabolites and their concentrations in tissues and body fluids. Differences in metabolism might be responsible for the discrepancies that have been observed in studies performed in vivo and in vitro using vitamin E as a REVIEW

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“…4,[7][8][9][10][11][12] CYP3A11 is the most studied isoform and is regulated by nuclear receptors pregnane X receptor (PXR) 13,14 and constitutive androstane receptor (CAR). 15,16 PXR, a novel orphan nuclear receptor, has been implicated in CYP3A subfamily induction in response to various xenobiotics.…”

Section: Introductionmentioning

confidence: 99%

“…10 Sakuma et al 10 cloned CYP3A41 and showed that the highest levels of CYP3A41 expression were reached after sexual maturation. Such a sexual dimorphism is interesting, and understanding the regulation of these genes will be the first step taken to elucidate gender-dependent clinical responses.…”

Section: Introductionmentioning

confidence: 99%

CAR/PXR provide directives for Cyp3a41 gene regulation differently from Cyp3a11

et al. 2004

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This study reports that Cyp3a41 gene contains 13 exons and is localized on the chromosome 5. CYP3A41 is a female-specific isoform that is predominantly expressed in the liver. Estrogen signaling is not responsible for its female specificity. CYP3A41 expression in kidney and brain is observed only in 50% of mice examined. PXR mediates dexamethasone-dependent suppression of CYP3A41. In contrast to CYP3A11, CYP3A41 expression is not induced by pregnenolone-16a-carbonitrile (PCN) in wild-type mice, but is significantly suppressed by PCN in PXR À/À mice. Phenobarbital and TCPOBOP induce CYP3A11 expression only in the presence of CAR, but have no effect on CYP3A41 expression. Immunoblot and erythromycin demethylase activity analysis reveal robust CYP3A induction after PCN treatment, which is poorly correlated to CYP3A41. These findings suggest a differential role for CAR/PXR in regulating individual CYP3A isoforms by previously characterized CYP3A inducers.

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A Novel Female-Specific Member of the CYP3A Gene Subfamily in the Mouse Liver

Cited by 72 publications

References 29 publications

Deregulated Hepatic Metabolism Exacerbates Impaired Testosterone Production in Mrp4-deficient Mice

Deregulated Hepatic Metabolism Exacerbates Impaired Testosterone Production in Mrp4-deficient Mice

Complexity of vitamin E metabolism

CAR/PXR provide directives for Cyp3a41 gene regulation differently from Cyp3a11

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