Developmental Expression of the Major Human Hepatic CYP3A Enzymes

Stevens, Jeffrey C.; Hines, Ronald N.; Gu, Chungang; Koukouritaki, Sevasti B.; Manro, Jason R.; Tandler, Peter J.; Zaya, Matthew J.

doi:10.1124/jpet.103.054841

Cited by 330 publications

(279 citation statements)

References 31 publications

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“…Hepatic CYP2C19 is largely responsible for demethylation of diazepam. This enzyme's expression and activity approach adult levels within ~6 mo (27). Levels of CYP3A4, the enzyme largely responsible for catalyzing diazepam hydroxylation, rise gradually during the first 6 mo, but remain lower in children up to 2 y of age than in adults (28).…”

Section: Discussionmentioning

confidence: 99%

Ontogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Ontogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin

et al. 2015

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“…8 CYP3A7 is predominantly a fetal enzyme, with high levels of expression in fetal liver and intestine, tapering off after birth in most. 9 CYP3A7 plays an important role in the metabolism of endogenous substrates, such as testosterone and dehydroepiandrosterone, as well as potentially toxic compounds such as retinoic acid. 10,11 The role of CYP3A7 in the metabolism and clearance of these and many exogenous substrates to which the fetus is exposed, as well as large inter-individual differences in fetal CYP3A7 expression level 12 have led to the suggestion that differences in CYP3A7 expression and/or activity could contribute to inter-individual differences in embryonic toxicity and teratogenicity.…”

Section: Introductionmentioning

confidence: 99%

Sequence diversity and haplotype structure at the human CYP3A cluster

et al. 2005

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The four members of the human CYP3A subfamily play important roles in the clearance of xenobiotics, hormones, and environmental compounds. Many SNPs at the CYP3A locus have been characterized, with several showing large allele frequency differences across populations. In addition to the effects of CYP3A SNPs on drug metabolism, recent studies have highlighted the potential for CYP3A variation in susceptibility to several common phenotypes, including hypertension and cancer. We previously showed that the CYP3A4 and CYP3A5 genes have a strong haplotype structure at varying frequencies across ethnic groups. Here, we extend our re-sequencing survey to the remaining CYP3A genes in the same cluster, CYP3A7 and CYP3A43. Our study identified a large number of SNPs in coding and conserved noncoding sequences, several of which are common. The combined data set allows us to investigate patterns of sequence variation and linkage disequilibrium at the entire CYP3A locus for use in future association studies.

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“…In addition to CYP3A4/5, CYP3A7 is known to be a major P450 isoform highly expressed in the fetal liver, 15,16) and a shift in hepatic CYP3A expression from CYP3A7 to CYP3A4 occurs after birth.…”

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confidence: 99%

“…15) The expression level of CYP3A7 is significant through 6 months postnatal age, 16) and it is also detectable in low amounts in some adult livers.…”

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confidence: 99%

“…15) The expression level of CYP3A7 is significant through 6 months postnatal age, 16) and it is also detectable in low amounts in some adult livers. 17) Given that both sildenafil and tadalafil are frequently administered to neonates and/or infant patients with PAH associated with congenital heart disease, basic information on the comparison of the kinetics of CYP3A7-catalyzed metabolism may be of interest to physicians treating children with these drugs.…”

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confidence: 99%

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Contribution of CYP3A Isoforms to Dealkylation of PDE5 Inhibitors: A Comparison between Sildenafil N-Demethylation and Tadalafil Demethylenation

Takahiro

Nakamura

Kohno

et al. 2015

Biological ^|^ Pharmaceutical Bulletin

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The aim of this study was to characterize the kinetics of metabolite formation of the phosphodiesterase type-5 (PDE5) inhibitors sildenafil and tadalafil by CYP3A4, CYP3A5, and CYP3A7 isoforms. The formations of N-desmethyl sildenafil and desmethylene tadalafil were examined using CYP3A supersomes co-expressing human P450 oxidoreductase and cytochrome b 5 . Both sildenafil N-demethylation and tadalafil demethylenation were catalyzed by CYP3A4, CYP3A5, and to a lesser extent by CYP3A7. The kinetics of desalkyl metabolite formation of the two drugs were well fitted to the Hill equation; however, the Hill coefficients (n) suggested CYP3A-mediated negative cooperativity. Next, we analyzed the kinetics with a two binding sites model assuming two reaction steps: reaction 1 with high-affinity and low-capacity metabolism and reaction 2 with low-affinity and high-capacity metabolism. The kinetics of desalkyl metabolite formation were also fitted to the two binding sites model 1) PDE5 inhibitors have been shown to be an effective vasodilator, and have been used widely as a treatment not only for erectile dysfunction, but also for pulmonary arterial hypertension (PAH).2) Sildenafil and tadalafil are orally active inhibitors of PDE5 that are approved for the treatment of PAH in Japan, but their half-life period in the body differs substantially.3,4) That is, sildenafil has a fairly short half-life of about 4-5 h, whereas tadalafil has a long half-life of about 17.5 h in healthy subjects.5,6) The short half-life of sildenafil makes it the drug of choice in patients with more severe cardiovascular disease, allowing early use of supportive treatment if an adverse clinical event occurs. 7) In contrast, tadalafil has the advantage of once a day dosing compared to sildenafil's three times a day dosing, with implications for patient convenience and compliance. 6,8) Therefore, a transition from sildenafil to tadalafil has been frequently tried in stable patients with PAH. 3,8) In humans, sildenafil is eliminated predominantly by hepatic metabolism and is converted to an active metabolite, N-desmethyl sildenafil, with properties similar to the parent drug.9) The N-demethylation by CYP3A is the major route of metabolism of sildenafil in humans 10) (Fig. 1). Recently, Ku et al. 11) showed that both CYP3A4 and CYP3A5 played a significant role in the metabolism of sildenafil using CYP3A supersomes. That is, the intrinsic clearance for N-dealkylation of sildenafil by CYP3A5 and CYP3A4 were 0.09 and 0.07 µL/ min/pmol P450, respectively. 11) They also demonstrated that the mean rate for N-desalkyl metabolite formation from sildenafil was high in human liver microsome preparations with CYP3A5 activity (heterozygous for CYP3A5*1/*3 alleles) compared to those with null CYP3A5 activity (homozygous for CYP3A5*3 allele).11) These results suggested that genetic polymorphism of CYP3A5 at least partly contributes to interindividual variability in the disposition of sildenafil. On the other hand, tadalafil is eliminated predominantly by oxidative me...

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Developmental Expression of the Major Human Hepatic CYP3A Enzymes

Cited by 330 publications

References 31 publications

Ontogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin

Ontogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin

Sequence diversity and haplotype structure at the human CYP3A cluster

Contribution of CYP3A Isoforms to Dealkylation of PDE5 Inhibitors: A Comparison between Sildenafil N-Demethylation and Tadalafil Demethylenation

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