Human cytochrome P450s involved in the metabolism of 9-cis- and 13-cis-retinoic acids

Marill, Julie; Capron, Claude; Idres, Nadia; Chabot, Guy G.

doi:10.1016/s0006-2952(01)00925-x

Cited by 74 publications

(54 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[ 14 C]Capravirine (2 M) was coincubated with both ritonavir (2 M) and one of the three chemical inhibitors, quercetin (for CYP2C8 at 0 or 30 M; Marill et al, 2002), sulfaphenazole (for CYP2C9 at 0 or 2 M; Back et al, 1988), and ticlopidine (for CYP2C19 at 0 or 10 M; Donahue et al, 1997) in human liver microsomes for 30 min at 37°C. All other incubation conditions and sample preparation procedures were the same as described above (Microsomal Metabolism).…”

Section: Phenotyping Of Capravirine Oxygenationsmentioning

confidence: 99%

Identification of Enzymes Responsible for Primary and Sequential Oxygenation Reactions of Capravirine in Human Liver Microsomes

Zhao²,

Kang³

et al. 2006

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Capravirine, a new non-nucleoside reverse transcriptase inhibitor, undergoes extensive oxygenation reactions, including N-oxidation, sulfoxidation, sulfonation, and hydroxylation in humans. Numerous primary (mono-oxygenated) and sequential (di-, tri-, and tetraoxygenated) metabolites of capravirine are formed via the individual or combined oxygenation pathways. In this study, cytochrome P450 enzymes responsible for the primary and sequential oxygenation reactions of capravirine in human liver microsomes were identified at the specific pathway level. The total oxygenation of capravirine is mediated predominantly (>90%) by CYP3A4 and marginally (<10%) by CYP2C8, 2C9, and 2C19 in humans. Specifically, each of the two major mono-oxygenated metabolites C23 (sulfoxide) and C26 (N-oxide), is mediated predominantly (>90%) by CYP3A4 and slightly (<10%) by CYP2C8, the minor tertiary hydroxylated metabolite C19 by CYP3A4, 2C8, and 2C19, and the minor primary hydroxylated metabolite C20 by CYP3A4, 2C8, and 2C9. However, all sequential oxygenation reactions are mediated exclusively by CYP3A4. Due to their relatively insignificant contributions of C19 and C20 to total capravirine metabolism, no attempt was made to determine relative contributions of cytochrome P450 enzymes to the formation of the two minor metabolites.

show abstract

Section: Phenotyping Of Capravirine Oxygenationsmentioning

confidence: 99%

Identification of Enzymes Responsible for Primary and Sequential Oxygenation Reactions of Capravirine in Human Liver Microsomes

Zhao²,

Kang³

et al. 2006

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…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. 13 Since CYP3A43 is expressed at very low levels in several tissues, including liver, prostate, and testis, 14 it is not believed to play a substantial role in drug metabolism and has not been investigated as extensively as other members of the subfamily.…”

Section: Introductionmentioning

confidence: 99%

Sequence diversity and haplotype structure at the human CYP3A cluster

et al. 2005

View full text Add to dashboard Cite

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.

show abstract

“…to rapid metabolism of ATRA (Budhu and Noy, 2002); (3) overexpression of HER2/Grb2/Akt pathway (Mendoza-Gamboa et al, 2004); and (4) metabolism of ATRA by cytochrome P450 (CYP)-dependent ATRA 4-hydoxylase enzymes namely CYP26 family, CYP2C8 and CYP3A4 (McSorley and Daly, 2000;Marill et al, 2002;Njar, 2002;Njar et al, 2006a, b). All-trans-retinoic acid is responsible for inducing the expression of cytochrome P450 enzymes leading to its catabolism.…”

mentioning

confidence: 99%

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

et al. 2007

View full text Add to dashboard Cite

Antitumour effects of retinoids are attributed to their influence on cell proliferation, differentiation, apoptosis and angiogenesis. In our effort to develop useful agents for breast cancer therapy, we evaluated the effects of four representative retinoic acid metabolism blocking agents (RAMBAs, VN/14-1, VN/50-1, VN/66-1 and VN/69-1) on growth inhibition of oestrogen receptor positive (ER þ ve, MCF-7 and T-47D) and oestrogen receptor negative (ER Àve, MDA-MB-231) human breast cancer cells. Additionally, we investigated the biological effects/molecular mechanism(s) underlying their growth inhibitory properties as well as their antitumour efficacies against MCF-7 and MCF-7Ca tumour xenografts in nude mice. We also assessed the effect of combining VN/14-1 and all-trans-retinoic acid (ATRA) on MCF-7 tumuor xenografts. The ER þ ve cell lines were more sensitive (IC 50 values between 3.0 and 609 nM) to the RAMBAs than the ER Àve MDA-MB-231 cell line (IC 50 ¼ 5.6 -24.0 mM). Retinoic acid metabolism blocking agents induced cell differentiation as determined by increased expression of cytokeratin 8/18 and oestrogen receptor-a (ER-a). Similar to ATRA, they also induced apoptosis via activation of caspase 9. Cell cycle analysis indicated that RAMBAs arrested cells in the G1 and G2/M phases and caused significant downregulation (480%) of cyclin D1 protein. In vivo, the growth of MCF-7 mammary tumours was dose-dependently and significantly inhibited (92.6%, Po0.0005) by VN/14-1. The combination of VN/14-1 and ATRA also inhibited MCF-7 breast tumour growth in vivo (up to 120%) as compared with single agents (Po0.025). VN/14-1 was also very effective in preventing the formation of MCF-7Ca tumours and it significantly inhibited the growth of established MCF-7Ca tumours, being as effective as the clinically used aromatase inhibitors, anastrozole and letrozole. Decrease in cyclin D1 and upregulation of cytokeratins, Bad and Bax with VN/14-1 may be responsible for the efficacy of this compound in inhibiting breast cancer cell growth in vitro and in vivo. Our results suggest that our RAMBAs, especially VN/14-1 may be useful novel therapy for breast cancer.

show abstract

Human cytochrome P450s involved in the metabolism of 9-cis- and 13-cis-retinoic acids

Cited by 74 publications

References 26 publications

Identification of Enzymes Responsible for Primary and Sequential Oxygenation Reactions of Capravirine in Human Liver Microsomes

Identification of Enzymes Responsible for Primary and Sequential Oxygenation Reactions of Capravirine in Human Liver Microsomes

Sequence diversity and haplotype structure at the human CYP3A cluster

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

Contact Info

Product

Resources

About