cDNA Cloning and Expression of a Novel Cytochrome P450 (CYP4F12) from Human Small Intestine

Hashizume, Takanori; Imaoka, Shingi; Hiroi, Toyoko; Terauchi, Yoshiaki; Fujii, Toshihiko; Miyazaki, Hisashi; Kamataki, Tetsuya; Funae, Yoshihiko

doi:10.1006/bbrc.2000.4238

Cited by 67 publications

(42 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It showed that the CYP4 enzymes v-hydroxylated the four PUFAs under study with different efficiencies. CYP4F12 proved to be about ten-and fifty-fold less efficient than CYP4A11 and CYP4F2, respectively, which is in agreement with the literature data (25). One should note that the activity value was so low that it was nearly at the limit of detection.…”

Section: Discussionsupporting

confidence: 91%

“…Furthermore, because of the differences in the CYP4 gene between mouse, rat, and humans (12), no information about the catalytic function of the human CYP4 enzymes can be inferred from the knowledge of the rat CYP4F (23) or Cyp4a mouse (24) enzymes. And finally, the CYP4s are mostly expressed in the liver and the kidney, except the CYP4F3A isoform, which is expressed in myeloid cells (16,21,25). Among the AA metabolites formed by human liver microsomes and other tissues, 20-HETE is the main one and frequently the most abundant (6,(26)(27)(28)(29).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism

Fer

Corcos

Dréano

et al. 2008

Journal of Lipid Research

View full text Add to dashboard Cite

Human CYP450 v-hydroxylases of the CYP4 family are known to convert arachidonic acid (AA) to its metabolite . This study deals with hydroxylations of four PUFAs, eicosatrienoic acid (ETA), AA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) by either human recombinant CYP4s enzymes or human liver microsomal preparations. CYP4F3A and CYP4F3B were the most efficient v-hydroxylases of these PUFAs. Moreover, the differences in the number of unsaturations of ETA, AA, and EPA allowed us to demonstrate a rise in the metabolic rate of hydroxylation when the double bond in 14-15 or 17-18 was missing. With the CYP4F enzymes, the main pathway was always the v-hydroxylation of PUFAs, whereas it was the (v-1)-hydroxylation with CYP1A1, CYP2C19, and CYP2E1. Finally, we demonstrated that the v9 and v3 PUFAs (ETA, EPA, and DHA) could all be used as alternative substrates in AA metabolism by human CYP4F2 and -4F3B. Thus, they decreased the ability of these enzymes to convert AA to 20-HETE. However, although ETA was the most hydroxylated substrate, EPA and DHA were the most potent inhibitors of the conversion of AA to 20-HETE. These findings suggest that some physiological effects of v3 FAs could partly result from a shift in the generation of active hydroxylated metabolites of AA through a CYP-mediated catalysis.-Fer, M., L. Corcos, Y. Dréano, E. Plée-Gautier, J-P. Salaün, F. Berthou, and Y. Amet. Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism. J. Lipid Res. 2008Res. . 49: 2379Res. -2389

show abstract

Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism

Fer

Corcos

Dréano

et al. 2008

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…Other P450s have been reported to be expressed in the human small intestine, including CYP2S1 (Rylander et al, 2001), CYP4F12, which catalyzes the antihistaminic ebastine's metabolism (Hashizume et al, 2001), and CYP2J2, which catalyzes arachidonic acid and ebastine metabolism (Zeldin et al, 1997).…”

Section: Human Small Intestine P450 Expressionmentioning

confidence: 99%

The Small Intestine as a Xenobiotic-Metabolizing Organ

Kaminsky

Zhang²

2003

Drug Metab Dispos

202

149

View full text Add to dashboard Cite

“…We determined the kinetic parameters for ebastine hydroxylation by the recombinant human CYP4F12 and CYP4F2, which were recently shown to be expressed in human small intestine and to participate in ebastine hydroxylation (Hashizume et al, 2001a). The K m and V max values of CYP4F12 were 3.0 M and 0.354 nmol/min/nmol P450, respectively.…”

Section: Metabolism Of Ebastine By Human Intestinal Microsomesmentioning

confidence: 99%

Involvement of CYP2J2 and CYP4F12 in the Metabolism of Ebastine in Human Intestinal Microsomes

Hashizume

Imaoka²,

Mise³

et al. 2002

J Pharmacol Exp Ther

Self Cite

149

128

View full text Add to dashboard Cite

The purpose of the study was to elucidate human intestinal cytochrome P450 isoform(s) involved in the metabolism of an antihistamine, ebastine, having two major pathways of hydroxylation and N-dealkylation. The ebastine dealkylase in human intestinal microsomes was CYP3A4, based on the inhibition studies with antibodies against CYP1A, CYP2A, CYP2C, CYP2D, CYP2E, and CYP3A isoforms and their selective inhibitors. However, ebastine hydroxylase could not be identified. We then examined the inhibitory effects of anti-CYP4F antibody and 17-octadecynoic acid, an inhibitor of the CYP4 family, on ebastine hydroxylation in intestinal microsomes, since CYP4F was recently found to be the predominant ebastine hydroxylase in monkey intestine; and a novel CYP4F isoform (CYP4F12), also capable of hydroxylating ebastine, was found to exist in human intestine. However, the inhibitory effects were only partial (about 20%) and thus it was thought that, although human CYP4F was involved in ebastine hydroxylation, another predominant enzyme exists. Further screening showed that the hydroxylation was inhibited by arachidonic acid. CYP2J2 was selected as a candidate expressed in the intestine and closely related to arachidonic acid metabolism. The catalytic activity of recombinant CYP2J2 was much higher than that of CYP4F12. Anti-CYP2J antibody inhibited the hydroxylation to about 70% in human intestinal microsomes. These results demonstrate that CYP2J2 is the predominant ebastine hydroxylase in human intestinal microsomes. Thus, the present paper for the first time indicates that, in human intestinal microsomes, both CYP2J and CYP4F subfamilies not only metabolize endogenous substrates but also are involved in the drug metabolism. Ebastine is a potent nonsedative H 1 -receptor antagonist (Fig. 1), and after oral administration to experimental animals and humans, the agent is almost completely metabolized to the pharmacologically active principle, the carboxylated metabolite (carebastine), and other inactive metabolites Matsuda et al., 1994;Yamaguchi et al., 1994). Carebastine alone was the major metabolite detectable in the blood. Our previous in situ studies using rats indicated that the small intestine extensively converted the orally given ebastine to carebastine via hydroxylated ebastine and the dealkylated metabolite (Fujii et al., 1997). Therefore, it seemed that small intestine plays an important role in the first-pass metabolism of this drug, and the enzymes responsible for its metabolism exist there.We reported that ebastine was primarily metabolized by human liver microsomes to two metabolites, hydroxy-and desalkyl-ebastine (Hashizume et al., 1998). N-Dealkylation to desalkyl-ebastine was mediated by CYP3A4, whereas hydroxylation to hydroxy-ebastine, the most important intermediate metabolite yielding carebastine, was mediated by unidentified P450(s) other than CYP3A4. Our recent studies revealed that two novel CYP4F isoforms (P450 MI-2 and CYP4F12) obtained from monkey and human small intestine, respectively, were ...

show abstract

cDNA Cloning and Expression of a Novel Cytochrome P450 (CYP4F12) from Human Small Intestine

Cited by 67 publications

References 21 publications

Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism

Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism

The Small Intestine as a Xenobiotic-Metabolizing Organ

Involvement of CYP2J2 and CYP4F12 in the Metabolism of Ebastine in Human Intestinal Microsomes

Contact Info

Product

Resources

About