Contribution of human hepatic cytochrome P450s and steroidogenic CYP17 to the N-demethylation of aminopyrine

Niwa, Toshiyuki; Sato, Ryo; Yabusaki, Yoshiyasu; Ishibashi, Fumihide; Katagiri, Masatoshi

doi:10.1080/004982599238731

Cited by 46 publications

(37 citation statements)

References 13 publications

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“…Microsomal CYP2B enzymes are implicated in the metabolism of morphine and lidocaine (43). Aminopyrine is a pain killer and antipyretic and is used in the treatment of acute leukemia; in humans, it is mainly metabolized by microsomal CYP2C19, CYP2C8, and CYP2D6 (44). Benzphetamine is an anorexiant used in the treatment of narcolepsy, obesity, and depression; this is metabolized principally by microsomal CYP4F enzymes (45).…”

Section: Erod Erndmentioning

confidence: 99%

Role of Protein Kinase C-mediated Protein Phosphorylation in Mitochondrial Translocation of Mouse CYP1A1, Which Contains a Non-canonical Targeting Signal

Dasari

Anandatheerthavarada

Robin

et al. 2006

Journal of Biological Chemistry

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A large number of mitochondrial proteins lack canonical mitochondrial-targeting signals. The bimodal transport of cytochromes P450 (CYPs) to endoplasmic reticulum and mitochondria (MT), reported previously by us, likely represents one mode of non-canonical protein targeting to MT. Herein, we have studied the mechanism of mouse MT-CYP1A1 targeting to gain insight into the regulatory features and evolutionary conservation of bimodal targeting mechanism. Mouse MT-CYP1A1 consists of two NH 2 -terminal-truncated molecular species, ؉91A1 and ؉331A1. Mutations Pro-2 3 Leu and Tyr-5 3 Leu, which increase the signal recognition particle ( Proteins targeted to mitochondria contain either NH 2 -terminal or internal signals, which include amphipathic ␣-helices, ␤-sheet, and random structures with spaced positively charged residues (1-3). A majority of the NH 2 -terminally located mitochondrial-targeting signals are cleaved by the mitochondrial matrix metalloprotease following their import, although in a number of cases the signals remain uncleaved (1-4). Recent proteomic studies indicate that yeast mitochondria contain as many as 800 proteins while the rodent heart and liver mitochondria may contain well over 1500 proteins (5-8). It is estimated that Ͼ50% of mitochondria-associated proteins in both yeast and mammalian cells lack canonical MT 4 -targeting signals, and the precise mode of targeting of these proteins as well as mechanism of their translocation across the MT membranes remain unclear. The bimodal targeting of CYPs to ER and MT, Alzheimer amyloid precursor protein to plasma membrane and MT, and translocation of cytosolic Glutathione S-transferases to MT (9 -14) may represent one mode of targeting of noncanonical signal containing proteins to the MT compartment.Recent studies from our laboratory showed that different xenobiotic-inducible CYPs such as rat CYP1A1, CYP2E1, and CYP2B1 and others that are widely recognized as microsomal proteins (MC-CYPs) are also targeted to varying degrees to mitochondria (9 -11). These studies led to the concept of a new family of chimeric non-canonical-targeting signals, which function both as ER-targeting and MT-targeting signals, under different physiological conditions. We proposed that bimodal targeting of these CYP proteins is facilitated by the cryptic MTtargeting signal domain (residues 29 -40), located between the transmembrane helical domain (residues 1-30) and the Prorich domain (residues 39 -44) in various members of the CYP1, CYP2, and CYP3 families. We have also shown that the cryptic MT-targeting signals of different CYPs are activated by two distinct mechanisms: (a) endoproteolytic cleavage of the NH 2 -

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Section: Erod Erndmentioning

confidence: 99%

Role of Protein Kinase C-mediated Protein Phosphorylation in Mitochondrial Translocation of Mouse CYP1A1, Which Contains a Non-canonical Targeting Signal

Dasari

Anandatheerthavarada

Robin

et al. 2006

Journal of Biological Chemistry

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“…We have reported the effect of BPA on human hepatic CYP activities using aminopyrine as a substrate, 9) because most CYPs show aminopyrine N-demethylase activity 13) ; the activities of CYPs except for CYP2E1 were inhibited by BPA. Additionally, BPA noncompetitively inhibited the aminopyrine N-demethylase activity by CYP2C8, and exhibited a mixed-type inhibition for S-mephenytoin 4-hydroxylation by CYP2C19.…”

Section: Discussionmentioning

confidence: 99%

“…Assay of Progesterone 17a a-Hydroxylase Activity Progesterone 17a-hydroxylase activity was determined by the methods described previously 13,16) with minor modification. Briefly, the membrane fraction containing CYP17 30 pmol and fp 2 90 pmol were preincubated at 37°C for 3 min, and the mixture was brought to 450 ml by addition of phosphate buffer 100 mM (pH 7.4), magnesium acetate 10 mM, and progesterone 1-50 mM.…”

Section: Expression Of Human Cyps and The Preparation Of Microsomes Amentioning

confidence: 99%

“…Recently, we reported that the aminopyrine Ndemethylase activity of CYP17 was comparable with that of CYP3A4, a dominant CYP in human liver. 13) This paper describes an in vitro investigation of BPA metabolism by human hepatic CYPs and steroidogenic CYP17 based on the disappearance rate of parent compounds from an incubation mixture and the inhibitory effect of BPA on the progesterone 17a-hydroxylase activity of CYP17. …”

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confidence: 99%

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Metabolism and Interaction of Bisphenol A in Human Hepatic Cytochrome P450 and Steroidogenic CYP17.

Niwa

Fujimoto

Kishimoto

et al. 2001

Biological & Pharmaceutical Bulletin

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Bisphenol A (4,4Ј-isopropylidenediphenol, BPA) is widely used in the chemical industry in the manufacturing of epoxy, polycarbonate, and polyester-styrene resins, and trace levels of BPA leach from polycarbonate plasticware and resins used for food packaging materials. This compound is suspected to be an endocrine disrupter. 2) Additionally, it has been reported that exposure of male rats and mice to BPA may be associated with increased incidence of cancers of the hematopoietic system and that high doses of BPA cause reproductive toxicity and affect cellular development in these species. 3,4) However, the effect of BPA in vivo and its mechanism of action are still unclear.Cytochrome P450 (CYP) comprises a superfamily of enzymes that catalyze the oxidation of a wide variety of xenobiotic chemicals including drugs, carcinogens, and steroids including sex hormones. [5][6][7] In the rat, BPA is metabolized to DNA-reactive bisphenol-o-quinone through 5-hydroxybisphenol and bisphenol semiquinone, 4) and the formation of the DNA adducts in a microsomal activation system is markedly decreased by CYP inhibitors, 8) suggesting that CYPs are closely associated with the metabolism and toxicity of BPA in rats. However, there are few reports on BPA metabolism in humans and on the human CYP(s) that metabolizes BPA.Recently, we reported that BPA inhibits human hepatic CYP-mediated drug-metabolizing activities including aminopyrine N-demethylation, especially by CYP2C8 and CYP2C19. 9) Additionally, Hanioka et al. reported that the administration of BPA to male rats decreased the catalytic activities and protein levels of male-specific CYP isoforms (such as CYP2C11 and CYP3A2) in rat liver microsomes, 10) and that BPA inhibited the drug-metabolizing activities of rat hepatic CYP1A2, CYP2A2, CYP2B2, CYP2C11, CYP2D1, CYP2E1, and CYP3A2. 11) CYP17 is found in the endoplasmic reticulum of the adrenal cortex and gonads, and mediates both 17a-hydroxylase and 17,20-lyase reactions of pregnenolone and progesterone, and is thus involved in the biosynthesis of glucocorticoids and sex hormones. 12) Therefore endocrine disrupters (sex hormone-like compounds) may affect the activity of CYP17. Recently, we reported that the aminopyrine Ndemethylase activity of CYP17 was comparable with that of CYP3A4, a dominant CYP in human liver. 13) This paper describes an in vitro investigation of BPA metabolism by human hepatic CYPs and steroidogenic CYP17 based on the disappearance rate of parent compounds from an incubation mixture and the inhibitory effect of BPA on the progesterone 17a-hydroxylase activity of CYP17. MATERIALS AND METHODS MaterialsBisphenol A was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Progesterone, 17a-hydroxyprogesterone, and estrone were from Sigma Chemical Co. (St. Louis, MO, U.S.A.). Human NADPH-cytochrome P450 reductase (fp 2 ) and hydrocortisone acetate were obtained from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). All other reagents were of the highest purity commercially available. Expression o...

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“…Here, we highlight a number of selected studies in which the potential of breath tests for CYP450 phenotyping has been evaluated by comparison with other indices of enzyme activity ( Table 1). The N-demethylation of aminopyrine, the first probe drug used in breath tests, is mediated by several CYP450 enzymes, with CYP2C19 being the most important isoform [122]. Kodaira et al found a significant correlation between AUC 0-3h of DOB 13 CO 2 / 12 CO 2 ratios and both plasma [ 13 C]-aminopyrine AUC 0-3h and clearance [123].…”

Section: Exhaled Breathmentioning

confidence: 99%

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

2015

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Interindividual variability in the expression and function of drug metabolizing cytochrome P (CYP) 450 enzymes, determined by a combination of genetic, non-genetic and environmental parameters, is a major source of variable drug response. Phenotyping by administration of a selective enzyme substrate, followed by the determination of a specific phenotyping metric, is an appropriate approach to assess the in vivo activity of CYP450 enzymes, as it takes into account all influencing factors. A phenotyping protocol should be as simple and convenient as possible. Typically, phenotyping metrics are determined in traditional matrices, such as blood, plasma or urine. Several sampling strategies have been proposed as an alternative for these traditional sampling techniques.In this review, we provide a comprehensive overview of available methods using dried blood spots, hair, oral fluid, exhaled breath and sweat for in vivo CYP450 phenotyping. We discuss the relation between phenotyping metrics measured in these samples and those in conventional matrices, along with the advantages and limitations of the alternative sampling techniques. Reliable phenotyping procedures for several clinically relevant CYP450 enzymes, including CYP1A2, CYP2C19 and CYP2D6, are currently available for oral fluid, breath or dried blood spots, while additional studies are needed for other CYP450 isoforms, such as CYP3A4. The role of hair analysis for this purpose remains to be established. Being non-or minimally invasive, these sampling strategies provide convenient and patient-friendly alternatives for classical phenotyping procedures, which may contribute to the implementation of CYP450 phenotyping in clinical practice. 4 Key Points Phenotyping by administration of a selective probe drug, followed by determination of a specific phenotyping metric, allows to assess the in vivo enzyme activity of CYP450 enzymes, taking into account genetic, non-genetic and environmental influencing factors. In addition to classical sampling techniques, such as blood or urine collection, reliable phenotyping procedures for several clinically relevant CYP450 enzymes are currently available for oral fluid, breath and dried blood spots.

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Contribution of human hepatic cytochrome P450s and steroidogenic CYP17 to the N-demethylation of aminopyrine

Cited by 46 publications

References 13 publications

Role of Protein Kinase C-mediated Protein Phosphorylation in Mitochondrial Translocation of Mouse CYP1A1, Which Contains a Non-canonical Targeting Signal

Role of Protein Kinase C-mediated Protein Phosphorylation in Mitochondrial Translocation of Mouse CYP1A1, Which Contains a Non-canonical Targeting Signal

Metabolism and Interaction of Bisphenol A in Human Hepatic Cytochrome P450 and Steroidogenic CYP17.

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

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