Cooperativity of<i>α</i>-naphthoflavone in cytochrome P450 3A-dependent drug oxidation activities in hepatic and intestinal microsomes from mouse and human

Emoto, Chie; Yamazaki, Hiroshi; Iketaki, Hitomi; Yamasaki, S.; Satoh, T; Shimizu, Robert W.; Suzuki, Susumu; Shimada, Noriaki; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1080/00498250110052120

Cited by 25 publications

(21 citation statements)

References 25 publications

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“…Interestingly, coincubation with the CYP1A2 inhibitor ␣-naphthoflavone (Chang et al, 1994) results in a slight increase in clindamycin sulfoxide formation compared with control. However, given that clindamycin is for all intents and purposes a CYP3A4 substrate and ␣-naphthoflavone has been demonstrated to act as an activator of CYP3A4 oxidation (Emoto et al, 2001;Shou et al, 2001), this observation is not surprising. Furthermore, ketoconazole, a potent CYP3A4 inhibitor (Newton et al, 1995;Sai et al, 2000), and cyclosporin A, a known CYP3A4 substrate (Pichard et al, 1991;Kelly et al, 1999), both markedly inhibited the oxidation of clindamycin, which provides additional evidence for the involvement of CYP3A4 in the biotransformation of clindamycin.…”

Section: Cyp1a2mentioning

confidence: 90%

In Vitro Metabolism of Clindamycin in Human Liver and Intestinal Microsomes

Wynalda¹,

Hutzler²,

Koets³

et al. 2003

Drug Metab Dispos

102

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Incubations with human liver and gut microsomes revealed that the antibiotic, clindamycin, is primarily oxidized to form clindamycin sulfoxide. In this report, evidence is presented that the Soxidation of clindamycin is primarily mediated by CYP3A. This conclusion is based upon several lines of in vitro evidence, including the following. 1) Incubations with clindamycin in hepatic microsomes from a panel of human donors showed that clindamycin sulfoxide formation correlated with CYP3A-catalyzed testosterone 6␤-hydroxylase activity; 2) coincubation with ketaconazole, a CYP3A4-specific inhibitor, markedly inhibited clindamycin S-oxidase activity; and 3) when clindamycin was incubated across a battery of recombinant heterologously expressed human cytochrome P450 (P450) enzymes, CYP3A4 possessed the highest clindamycin S-oxidase activity. A potential role for flavin-containing monooxygenases (FMOs) in clindamycin S-oxidation in human liver was also evaluated. Formation of clindamycin sulfoxide in human liver microsomes was unaffected either by heat pretreatment or by chemical inhibition (e.g., methimazole). Furthermore, incubations with recombinant FMO isoforms revealed no detectable activity toward the formation of clindamycin sulfoxide. Beyond identifying the drug-metabolizing enzyme responsible for clindamycin S-oxidation, the ability of clindamycin to inhibit six human P450 enzymes was also evaluated. Of the P450 enzymes examined, only the activity of CYP3A4 was inhibited (ϳ26%) by coincubation with clindamycin (100 M). Thus, it is concluded that CYP3A4 appears to account for the largest proportion of the observed P450 catalytic clindamycin S-oxidase activity in vitro, and this activity may be extrapolated to the in vivo condition.Clindamycin (methyl 7-chloro-6,7,8-trideoxy-6-[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carboxamido]-1-thio-1-threo-D-galacto-octopyranoside monohydrochloride) is an antibiotic of the "lincosamide" class (Brodasky et al., 1968). The lincosamide antibiotics seem to be most useful against the bacteria classified as Gram-positive cocci. In addition, clindamycin is helpful against protozoans such as Toxoplasma and Mycoplasma as well as many anaerobic bacteria (Luft and Remington, 1988;Dannemann et al., 1991;Mazur et al., 1999).In humans, absorption of clindamycin is rapid and virtually complete (90%) following oral administration (DeHaan et al., 1972;Metzler et al., 1973). Concentrations of clindamycin in the serum increase linearly with increased dose, and levels exceed the minimum inhibitory concentration for most indicated organisms for at least 6 h following administration of the recommended dose. Clindamycin is widely distributed throughout the body and has an average biological half-life of 2.4 h. The major bioactive metabolites excreted in urine and feces are clindamycin sulfoxide and N-desmethylclindamycin (Seaberg et al., 1984;Flaherty et al., 1988;Gatti et al., 1998).To date, there are no published reports tha...

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Section: Cyp1a2mentioning

confidence: 90%

In Vitro Metabolism of Clindamycin in Human Liver and Intestinal Microsomes

Wynalda¹,

Hutzler²,

Koets³

et al. 2003

Drug Metab Dispos

102

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“…Male Wistar rats, 7 weeks old, were obtained from Japan SLC (Shizuoka, Japan). Pooled microsomes and cytosol from five rat livers (RLM and RLC) and jejunums (RJM and RJC) were prepared according to the method of Emoto et al (2001).…”

Section: Methodsmentioning

confidence: 99%

Different Inhibitory Effects in Rat and Human Carboxylesterases

Takahashi

Katoh²,

Saitoh³

et al. 2009

Drug Metab Dispos

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ABSTRACT:In vitro inhibition studies on drug-metabolizing enzyme activity are useful for understanding drug-drug interactions and for drug development. However, the profile of the inhibitory effects of carboxylesterase (CES) activity has not been fully investigated concerning species and tissue differences. In the present study, we measured the inhibitory effects of 15 drugs and 1 compound on CES activity using liver and jejunum microsomes and cytosol in human and rat. In addition, the inhibition constant (K i values) and patterns were determined for the compounds exhibiting strong inhibition. Hydrolysis of imidapril and irinotecan hydrochloride (CPT-11) is catalyzed mainly by CES1 and CES2, respectively. In the inhibition study, imidaprilat formation from imidapril in human liver was strongly inhibited by nordihydroguaiaretic acid (NDGA) and procainamide. The inhibition profile and pattern were similar in human liver and rat liver. The compounds showing potent inhibition were similar between liver and jejunum. The K i value of NDGA (K i ‫؍‬ 13.3 ؎ 1.5 M) in human liver microsomes was 30-fold higher than that in rat liver microsomes (K i ‫؍‬ 0.4 ؎ 0.0 M). On the other hand, 7-ethyl-10-hydroxycamptothecin (SN-38) formation from CPT-11 was not inhibited except by carvedilol, manidipine, and physostigmine. The K i value of physostigmine (K i ‫؍‬ 0.3 ؎ 0.0 M) in human jejunum cytosol was 10-fold lower than that in rat jejunum cytosol (K i ‫؍‬ 3.1 ؎ 0.4 M) and was similar to that for manidipine. The present study clarified the species differences in CES inhibition. These results are useful for the development of prodrugs.

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“…For example, alpha-naphthoflavone inhibits CYP1A1 and CYP1A2, but stimulates CYP3A4 (Slaga et al, 1977;Emoto et al, 2001). Quercetin inhibits CYP1A1 (Moon et al, 2006).…”

Section: Direct Effects On P450 Activitymentioning

confidence: 99%

Effects of food natural products on the biotransformation of PCBs

James

Sacco

Faux

2008

Environmental Toxicology and Pharmacology

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Many food products, particularly fruits and vegetables, contain natural products that affect biotransformation enzymes. These may be expected to affect the rate of biotransformation of PCBs that are metabolized by the affected enzymes. The first step in PCB metabolism is cytochrome P450-dependent monooxygenation. Natural products present in cruciferous vegetables have been shown to selectively up-regulate CYP1A1 and CYP1A2 isozymes on chronic ingestion, and may lead to increased metabolism of those PCB congeners that are substrates for the induced P450s. On the other hand, several natural products selectively inhibit monooxygenation, especially in the intestine, and may lead to increased bioavailability and reduced metabolism of dietary PCBs. Food natural products are known to affect phase II pathways important in the detoxication of hydroxylated PCBs, namely UDP-glucuronosyltransferase and PAPS-sulfotransferase. Continual dietary exposure to chrysin and quercetin, found in fruits and vegetables, induces UGT1A1 and may reduce exposure to hydroxylated PCBs through increased glucuronidation. These and other natural products are also inhibitors of glucuronidation and sulfonation, potentially leading to transient decreases in the elimination of hydroxylated PCBs. In summary, the expected effects of food natural products on PCB biotransformation are complex and may be biphasic, with initial inhibition followed by enhanced biotransformation through monooxygenation and conjugation pathways.

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Cooperativity ofα-naphthoflavone in cytochrome P450 3A-dependent drug oxidation activities in hepatic and intestinal microsomes from mouse and human

Cited by 25 publications

References 25 publications

In Vitro Metabolism of Clindamycin in Human Liver and Intestinal Microsomes

In Vitro Metabolism of Clindamycin in Human Liver and Intestinal Microsomes

Different Inhibitory Effects in Rat and Human Carboxylesterases

Effects of food natural products on the biotransformation of PCBs

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