Effects of age and gender on in vitro properties of human liver microsomal monooxygenases

Schmucker, Douglas L.; Woodhouse, K.W.; Wang, Rose K.; Wynne, Hilary; James, Oliver; McManus, Michael E.; Kremers, Pierre

doi:10.1038/clpt.1990.164

Cited by 191 publications

(101 citation statements)

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“…Several lines of evidence indicate that the metabolism of several clinical drugs, mainly oxidized by CYP3A4, is more efficient in women than in men (Greenblatt et al, 1980;Watkins et al, 1989;Gorski et al, 1998). Recent studies show that women have higher hepatic CYP3A4 content and drug-metabolizing capacity than men (Wolbold et al, 2003); however, this conclusion is opposed by other observations (Schmucker et al, 1990;George et al, 1995).…”

contrasting

confidence: 52%

Growth Hormone Determines Sexual Dimorphism of Hepatic Cytochrome P450 3A4 Expression in Transgenic Mice

Cheung

Chen

et al. 2005

J Pharmacol Exp Ther

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The impact of age and sex on the expression of hepatic cytochrome P450 3A4 (CYP3A4) was recently determined in a transgenic mouse line carrying the human CYP3A4 gene. To further investigate the physiological regulation of human CYP3A genes, a novel transgenic mouse line was generated using a bacterial artificial chromosome clone containing both CYP3A4 and CYP3A7 genes. CYP3A7 expression was observed in transgenic mouse fetal livers, whereas CYP3A4 exhibited developmental expression characterized by sexual dimorphism in postpubertal livers. Hepatic CYP3A4 protein and RNA were expressed in immature transgenic male mice and became undetectable after 6 weeks of age, whereas CYP3A4 was expressed in both immature and adult females. CYP3A4 was markedly elevated by the xenobiotic receptor activator phenobarbital in both male and female livers, demonstrating drug induction of the CYP3A4 transgene in this mouse model. Furthermore, continuous infusion of recombinant growth hormone (GH) in transgenic male mice, overriding the pulsatile male plasma GH profile, increased hepatic CYP3A4 mRNA and protein to normal female levels. Continuous GH treatment also feminized the expression of endogenous murine Cyp2b and Cyp3a44 genes. Thus, human CYP3A4 contains all of the gene regulatory sequences required for it to respond to endogenous hormonal regulators of developmental expression and sexual dimorphism, in particular GH. These findings may help elucidate the role of GH in determining the sex-dependent expression of CYP3A4 in human liver and suggest that GH therapy may alter the pharmacokinetic and pharmacodynamic properties of CYP3A4 substrates, leading to enhanced metabolism and disposition of drugs in men.

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contrasting

confidence: 52%

Growth Hormone Determines Sexual Dimorphism of Hepatic Cytochrome P450 3A4 Expression in Transgenic Mice

Cheung

Chen

et al. 2005

J Pharmacol Exp Ther

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“…A recent study of 94 surgical liver samples found 2-fold higher CYP3A4 protein content and higher expression of CYP3A4 mRNA transcripts in female compared with male samples (61). In contrast, other studies in human livers observed no sex differences in CYP3A (62,63). Regardless of apparent sex-related differences in CYP3A activity, the same range of wide interpatient variation in CYP3A activity was observed in both female and male cancer patients ( Table 4), indicating that dosing strategies for drugs cleared by CYP3A should focus on the individual and not necessarily sex.…”

Section: Discussionmentioning

confidence: 75%

Factors Affecting Cytochrome P-450 3A Activity in Cancer Patients

Baker

Schaik

Rivory³

et al. 2004

Clinical Cancer Research

119

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Purpose: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patientsExperimental Design: A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6).Results: CYP3A activity (AUC 0 -40min ) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P > 0.2954). CYP3A activity was reduced by ϳ50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P < 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P > 0.05), but liver function combined with the concentration of the acute-phase reactant, ␣-1 acid glycoprotein, explained ϳ18% of overall variation in CYP3A activity (P < 0.001).Conclusions: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.

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“…The increase in CYP3A4 catalytic activity observed in confluent Huh7 cells can be explained by the concomitant and time-dependent increase of CYP3A4 and its electron donor POR. It is believed that under certain conditions, POR can be the rate-limiting factor for P450 activity, because the POR protein is expressed at much lower stoichiometric amounts than the P450s in the liver (Schmucker et al, 1990). Like POR, CYB5A, another well known modulator of CYP3A4 activity (Gan et al, 2009), also gradually increased with time of confluence, although it could not be detected until 3 weeks of confluence.…”

Section: Discussionmentioning

confidence: 99%

CYP3A4 Catalytic Activity Is Induced in Confluent Huh7 Hepatoma Cells

Sivertsson¹,

Ek²,

Darnell³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Drug-induced hepatotoxicity is an important cause for disapproval, limitations of use, or withdrawal of drugs, and there is a high need for reproducible in vitro systems that can predict such toxicity. In this study, we show that confluent growth of the human hepatoma cell line Huh7 up to 5 weeks results in increased gene expression of several cytochromes P450 (P450s), UDP-glucuronosyltransferases, transporters, transcription factors, and several liver-specific genes, as measured by low-density array. The most striking effect was seen for CYP3A4 expression. Western blot analysis revealed increased amounts of CYP3A4 together with increased levels of NADPH-P450 reductase, cytochrome b 5 , and albumin with prolonged time of confluence. By using the CYP3A4-specific substrates luciferin 6 benzyl ether, testosterone, and midazolam, we could confirm that the increased CYP3A4 gene expression also was accompanied by a similar increase in catalytic activity, inhibitable by the CYP3A4-selective inhibitor ketoconazole. The CYP3A4 activity in confluent cells was also inducible by rifampicin. Finally, the cell system could support the CYP3A4-dependent hepatotoxic activation of aflatoxin B 1 , which was effectively inhibited by ketoconazole. Our results show that Huh7 cells grown confluent differentiate into a more metabolically competent cell line, especially with regard to CYP3A4.

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Effects of age and gender on in vitro properties of human liver microsomal monooxygenases

Cited by 191 publications

References 0 publications

Growth Hormone Determines Sexual Dimorphism of Hepatic Cytochrome P450 3A4 Expression in Transgenic Mice

Growth Hormone Determines Sexual Dimorphism of Hepatic Cytochrome P450 3A4 Expression in Transgenic Mice

Factors Affecting Cytochrome P-450 3A Activity in Cancer Patients

CYP3A4 Catalytic Activity Is Induced in Confluent Huh7 Hepatoma Cells

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