SELECTIVITIES OF HUMAN CYTOCHROME P450 INHIBITORS TOWARD RAT P450 ISOFORMS: STUDY WITH cDNA-EXPRESSED SYSTEMS OF THE RAT

Kobayashi, Kaoru; Urashima, Kikuko; Shimada, Noriaki; Chiba, Kazuhiro

doi:10.1124/dmd.31.7.833

Cited by 93 publications

(74 citation statements)

References 11 publications

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“…Furafylline, a 1A2 inhibitor, did not inhibit synthesis. Ketoconazole is an effective inhibitor of 1A2 in rats (Kobayashi et al, 2003) and was the only other agent that significantly inhibited demethyl-IQ synthesis at a concentration of 0.02 mM. Additional studies are needed to distinguish the specific P450(s) involved.…”

Section: Lakshmi Et Almentioning

confidence: 99%

Identification of New 2-Amino-3-methylimidazo[4,5-f]quinoline Urinary Metabolites from β-Naphthoflavone-Treated Mice

Lakshmi

Hsu²,

Zenser

2009

Drug Metab Dispos

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Cancer etiology and human risk estimates suggest that our diet contains mutagenic and carcinogenic chemicals that are agents in human cancer. Examples of these agents are aflatoxin B 1 , which is formed by fungi growing on poorly stored grain and associated with liver cancer (Groopman et al., 1988). Benzo[a]pyrene, a product of incomplete combustion of organic material, can deposit on food from fat dripping onto the coals during cooking or as a result of charring of food. These and other polycyclic aromatic hydrocarbons have been associated with several types of tumors (IARC, 1983). Heterocyclic amines (HCAs) are another class of dietary carcinogens (Felton and Knize, 1990). These chemicals are produced by high-temperature cooking of meat and derived from amino acids, creatine, and glucose present in meat. More than 17 different HCAs have been isolated from cooked meat. Studies have identified breast, colon, and bladder as possible target organs of HCAs and recently designated 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) as "reasonably anticipated to be a human carcinogen" (National Toxicology Program Report on Carcinogens: Background Document for Heterocyclic Amines: MeIQ, MeIQx, IQ, and PhIP, 2005; http://ntp.niehs.nih.gov/ntp/roc/eleventh/ profiles/s092vhca.pdf).IQ is an HCA. Studies in nonhuman primates given IQ showed a 95% incidence of hepatocarcinomas (Adamson et al., 1994). Additional studies in mice and rats have shown tumor formation in multiple tissues (Sugimura, 2000). Exposure to HCAs varies depending on cooking techniques, temperature, time, and the type and amount of meat consumed with individuals potentially exposed to micrograms of these amines per day (Felton and Knize, 1990;Pais et al., 1999). Current knowledge underlying the mechanism of HCA carcinogenesis indicates interplay of activation and detoxification pathways.IQ activation requires N-oxidation by cytochrome P450 (P450), followed by O-acetylation with subsequent formation of a reactive intermediate, nitrenium ion, which binds DNA and initiates carcinogenesis (Turesky et al., 1991). N-OH-IQ is detected as a microsomal oxidation product (Turesky et al., 1991) but is not detected in urine because of its lability. Bacteria expressing human P450 1A2 and N-acetyltransferase activate IQ to a mutagen(s), mimicking the in vivo

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Section: Lakshmi Et Almentioning

confidence: 99%

Identification of New 2-Amino-3-methylimidazo[4,5-f]quinoline Urinary Metabolites from β-Naphthoflavone-Treated Mice

Lakshmi

Hsu²,

Zenser

2009

Drug Metab Dispos

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“…Although TAO is known as a potent and specific CYP3A inhibitor (Kostrubsky et al, 1997;Crincoli et al, 2008), KTZ has been reported to inhibit potently not only CYP3A1/2 activities but also CYP2C11 activity by a study using vaculovirus-infected insect cells expressing each rat P450 (Kobayashi et al, 2003). To examine whether KTZ treatment affected hepatic CYP3A and CYP2C enzyme activities in the rats, MDZ and TOL hydroxylase activities were measured in the microsomes prepared from livers collected 1.5 hours after the KTZ administration in rats administered CBZ at a dose of 400 mg/kg once daily for 4 days.…”

Section: Hepatotoxicity By Carbamazepine Requires Metabolism In Rats 963mentioning

confidence: 99%

Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats

et al. 2015

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Carbamazepine (CBZ) is widely used as an antiepileptic agent and causes rare but severe liver injury in humans. It has been generally recognized that reactive metabolites formed via the metabolic activation reaction contribute to the onset of liver injuries by several drugs. However, the role of CBZ metabolism in the development of liver injury is not fully understood. In this study, we developed a novel rat model of CBZ-induced liver injury and attempted to elucidate the associated mechanisms by focusing on the metabolism of CBZ. The repeated administration of CBZ for 5 days in combination with L-buthionine sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, resulted in increases in the plasma alanine aminotransferase (ALT) levels and centrilobular necrosis in the liver that were observed in various degrees. The CBZ and 2-hydroxy-CBZ concentrations in the plasma after the last CBZ administration were lower in the rats with high plasma ALT levels compared with those with normal plasma ALT levels, showing the possibility that the further metabolism of CBZ and/ or 2-hydroxy-CBZ is associated with the liver injury. Although a single administration of CBZ did not affect the plasma ALT levels, even when cotreated with BSO, pretreatment with dexamethasone, a CYP3A inducer, increased the plasma ALT levels. In addition, the rats cotreated with troleandomycin or ketoconazole, CYP3A inhibitors, suppressed the increased plasma ALT levels. In conclusion, reactive metabolite(s) of CBZ produced by CYP3A under the GSH-depleted condition might be involved in the development of liver injury in rats.

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“…These drugs also show a range of metabolic clearance values (Table 1), allowing enzymetransporter interplay to be assessed. The probes selected as markers of inhibition in the two systems were midazolam (for the CYP3A and CYP2C families) and theophylline (for the CYP1A family) (Kobayashi et al, 2003;Chovan et al, 2007). Comparison of inhibition parameters allows a cell/medium partition coefficient (Kp) to be determined that can be interpreted using previously proposed models for enzyme-transporter interplay (Liu and Pang, 2005;Shitara et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Comparative Use of Isolated Hepatocytes and Hepatic Microsomes for Cytochrome P450 Inhibition Studies: Transporter-Enzyme Interplay

Brown¹,

Wilby²,

Alder³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Accurate assignment of the concentration of victim drug/inhibitor available at the enzyme active site, both in vivo and within an in vitro incubation, is an essential requirement in rationalizing and predicting drug-drug interactions. Inhibitor accumulation within the liver, whether as a result of active transport processes or intracellular binding, may best be accounted for using hepatocytes rather than hepatic microsomes to estimate in vitro inhibitory potency. The aims of this study were to compare K i values determined in rat liver microsomes and freshly isolated rat hepatocytes of four cytochrome P450 (P450) inhibitors (clarithromycin, enoxacin, nelfinavir, and saquinavir) with known hepatic transporter involvement and a range of uptake (cell/medium concentration ratios 20-3000) and clearance (10-1200 l/min/10 6 cells) properties.Inhibition studies were performed using two well established P450 probe substrates (theophylline and midazolam). Comparison of unbound K i values showed marked differences between the two in vitro systems for inhibition of metabolism. In two cases (clarithromycin and enoxacin, both low-clearance drugs), inhibitory potency in hepatocytes markedly exceeded that in microsomes (10-to 20-fold), and this result was consistent with their high cell/medium concentration ratios. For nelfinavir and saquinavir (high-clearance, extensively metabolized drugs), the opposite trend was seen in the K i values: despite very high cell/medium concentration ratios, stronger inhibition was evident within microsomal preparations. Hence, the consequences of hepatic accumulation resulting from uptake transporters vary according to the clearance of the inhibitor. This study demonstrates that transporter-enzyme interplay can result in differences in inhibitory potency between microsomes and hepatocytes and hence drug-drug interaction predictions that are not always intuitive.

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SELECTIVITIES OF HUMAN CYTOCHROME P450 INHIBITORS TOWARD RAT P450 ISOFORMS: STUDY WITH cDNA-EXPRESSED SYSTEMS OF THE RAT

Cited by 93 publications

References 11 publications

Identification of New 2-Amino-3-methylimidazo[4,5-f]quinoline Urinary Metabolites from β-Naphthoflavone-Treated Mice

Identification of New 2-Amino-3-methylimidazo[4,5-f]quinoline Urinary Metabolites from β-Naphthoflavone-Treated Mice

Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats

Comparative Use of Isolated Hepatocytes and Hepatic Microsomes for Cytochrome P450 Inhibition Studies: Transporter-Enzyme Interplay

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