Procarcinogen activation by cytochrome P450 3A4 and 3A5 expressed in <i>Escherichia coli</i> and by human liver microsomes

Yamazaki, Hiroshi; Inui, Yukiharu; Wrighton, Steven; Guengerich, F. Peter; Shimada, Tsutomu

doi:10.1093/carcin/16.9.2167

Cited by 53 publications

(28 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…CYP3A proteins have been assigned as the site of biotransformation of many drugs and procarcinogens [7,[38][39][40]. The high degree of similarity between the three major isoforms belonging to the CYP3A subfamily made any comparison of the substrate specificity of each isoform difficult.…”

Section: Discussionmentioning

confidence: 99%

Expression of CYP3A in the Human Liver — Evidence that the Shift between CYP3A7 and CYP3A4 Occurs Immediately After Birth

Lacroix

Sonnier

Moncion

et al. 1997

European Journal of Biochemistry

472

344

View full text Add to dashboard Cite

CYP3A isoform? are responsible for the biotransformation of a wide variety of exogenous chemicals and endogenous steroids in human tissues. Two members of the CYP3A subfamily display developmentally regulated expression in the liver; CYP3A7 is expressed in the fetal liver, whereas CYP3A4 is the major cyrochrome P-450 isoform present in the adult liver. To gain insight into the descriptive ontogenesis of CYP3A isoforms during the neonatal period, we have developed several approaches to explore a neonatal liver bank. Although CYP3A4 and CYP3A7 are structurally closely related, they differ in their capacity to carry out monooxygenase reactions. We have cloned CYP3A4 and CYP3A7 and established stable transfectants in Ad293 cells to investigate their substrate specificities. The 16a hydroxylation of dehydroepiandrosterone is catalyzed by both proteins, but CYP3A7 has a higher affinity and maximal velocity than CYP3A4. Conversely, the conversion of testosterone into its 6p derivative is essentially supported by CYP3A4. We used these two probes to determine the ontogenic evolution at the protein level; CYP3A7 was very active in the fetal liver and its activity was maximal during the first week following birth before to progressively decline and reached a very low level in adult livers. Conversely, the activity of CYP3A4 was extremely weak in the fetus and began to raise after birth to reach 30-40% of the adult activity after one month.CYP3A4 RNA accumulation displays a similar pattern of evolution; when probed with an oligonucleotide, its concentration increased rapidly after birth to reach a plateau as soon as the first week of age.These data supports the assumption that CYP3A4 expression is transcriptionally activated during the first week after birth and is accompanied by a simultaneous decrease of CYP3A7 expression, in such a way that the overall CYP3A protein content and the level of pentoxyresorufin dealkylase catalyzed by the two proteins remain nearly constant.Keywords: ontogenesis ; human liver; CYP3A7, CYP3A4 ; dehydroepiandrosterone.The cytochrome P-450 (P-450) gene superfamily encodes a group of hemoproteins that mostly catalyze the oxidative metabolism of hydrophobic endogenous compounds such as steroids, fatty acids, prostaglandins and exogenous chemicals including drugs, carcinogens and environmental pollutants. These substrates can be converted in presence of NADPH and molecular oxygen either to inert polar metabolites, further eliminated in a water-soluble form, or to cytotoxic or carcinogenic derivatives. One feature of the P-450 system is its capacity to act on thousands of compounds and to carry out a multiplicity of reactions, generically termed monooxygenations. To cope with the large number of substrates and the wide diversity of their chemical structures, several isoforms of P-450 coexist [l, 21 and exhibit overlapping substrate specificities (for review, see [3]). In the human liver, one can consider that the major P-450 isoforms are members of the CYP2C and CYP3A subfamilies. They are constitu...

show abstract

Section: Discussionmentioning

confidence: 99%

Expression of CYP3A in the Human Liver — Evidence that the Shift between CYP3A7 and CYP3A4 Occurs Immediately After Birth

Lacroix

Sonnier

Moncion

et al. 1997

European Journal of Biochemistry

472

344

View full text Add to dashboard Cite

show abstract

“…Compared with CYP3A4, the CYP3A5 enzyme shows roughly the same substrate preference pattern but lower turnover rates (Aoyama et al, 1989;Wrighton et al, 1990;Yamazaki et al, 1995). However, CYP3A5 cannot metabolize some CYP3A4 substrates, such as erythromycin and quinidine (Wrighton et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Regulation of CYP3A5 by Glucocorticoids and Cigarette Smoke in Human Lung-Derived Cells

Hukkanen

Väisänen²,

Lassila³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

CYP3A5 is the major CYP3A form in the human lung, and it is inducible by dexamethasone in the human A549 lung adenocarcinoma cell line. In the present study, we characterized the nature and mechanism of this induction process. The induction of CYP3A5 mRNA was assessed by quantitative reverse transcriptase-polymerase chain reaction in A549 cells. About 4-fold induction was detected by nanomolar concentrations of dexamethasone and also by budenoside and beclomethasone dipropionate, glucocorticoids used for the inhalation treatment of bronchial asthma, whereas the CYP3A4 inducers mifepristone (RU486), rifampicin, clotrimazole, and nifedipine were without effect. The glucocorticoid induction was blocked by the glucocorticoid receptor (GR) antagonist RU486. In transient transfection assays to A549 cells, CYP3A5 5Ј regulatory region was activated by the dexamethasone treatment. In contrast, dexamethasone was unable to induce CYP3A5 transcription in GR-deficient COS-1 cells, but the induction could be achieved after GR cotransfection. The CYP3A5 expression was measured in alveolar macrophages from patients with respiratory diseases. The CYP3A5 expression level was decreased by smoking, but glucocorticoid therapy had no statistically significant effect. In conclusion, CYP3A5 is induced in the A549 cells by glucocorticoids through a GR-mediated pathway, whereas smoking may be able to depress CYP3A5 expression.

show abstract

“…Like AFB 1 , STC has been found to be metabolized by the cytochrome P4503A4 (Yamazaki et al, 1995) system to an active epoxide, which can then interact with nucleic acids to form a DNA-adduct at the N 7 -− guanyl position in the target cells (Essigmann et al, 1979(Essigmann et al, , 1980(Essigmann et al, , 1982Terao, 1983).…”

Section: -467mentioning

confidence: 99%

Scientific information on mycotoxins and natural plant toxicants

Battilani

Costa

Dossena

et al. 2009

EFSA Supporting Publications

View full text Add to dashboard Cite

Procarcinogen activation by cytochrome P450 3A4 and 3A5 expressed in Escherichia coli and by human liver microsomes

Cited by 53 publications

References 0 publications

Expression of CYP3A in the Human Liver — Evidence that the Shift between CYP3A7 and CYP3A4 Occurs Immediately After Birth

Expression of CYP3A in the Human Liver — Evidence that the Shift between CYP3A7 and CYP3A4 Occurs Immediately After Birth

Regulation of CYP3A5 by Glucocorticoids and Cigarette Smoke in Human Lung-Derived Cells

Scientific information on mycotoxins and natural plant toxicants

Contact Info

Product

Resources

About