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A Guillouzo

Publications and source records attributed to A Guillouzo.

At least 19 recordsLinked to original sources
PubMed2002

The drug efflux pump MRP2: regulation of expression in physiopathological situations and by endogenous and exogenous compounds.

The multidrug resistance-associated protein 2 (MRP2) is an ATP-binding cassette transporter involved in biliary, renal, and intestinal secretion of numerous organic anions, including endogenous compounds such as bilirubin and exogenous compounds such as drugs and toxic chemicals. Its expression can be modulated in various physiopathological situations, notably being markedly decreased during liver cholestasis and upregulated in some cancerous tissues. In addition, MRP2 levels are altered in hepatocytes in response to hormones such as glucocorticoids and to structurally unrelated drugs such as rifampicin, phenobarbital, ritonavir, and cisplatin. The chemical carcinogen 2-acetylaminofluorene and chemopreventive agents such as oltipraz and sulforaphane also markedly increased MRP2 expression in liver parenchymal cells. Interestingly, most of the chemical inducers of MRP2 act on drug-metabolizing enzymes, indicating a coordinated regulation of these detoxifying proteins; cellular mechanisms involved are, at least partly, common and may be related to nuclear hormone receptors such as the pregnane X receptor. Owing to the major role played by MRP2 in elimination of drugs and endogenous compounds, modulation of its expression may lead to adverse effects or to changes in drug pharmacokinetics.

Animals↗
PubMed2001

Resistance of human multidrug resistance-associated protein 1-overexpressing lung tumor cells to the anticancer drug arsenic trioxide.

The human multidrug-resistance protein (MRP1) confers resistance to some heavy metals such as arsenic and antimony, mainly through mediating an increased cellular efflux of metal. However, it was recently suggested that arsenic, used under its trioxide derivative form as anticancer drug, is not handled by MRP1. The aim of the present study was to test this hypothesis in MRP1-overexpressing human lung tumor GLC4/Sb30 cells. Using the cytotoxicity MTT assay, GLC4/Sb30 cells were found to be 10.8-fold more resistant to arsenic trioxide (As2O3) than parental GLC4 cells. MK571, a potent inhibitor of MRP1 activity, almost totally reversed resistance of GLC4/Sb30 cells, but did not alter the sensitivity of GLC4 cells. Moreover, As2O3-loaded GLC4/Sb30 cells poorly accumulated arsenic through an increased MK571-sensitive efflux of metal. Finally, depletion of cellular glutathione levels in buthionine sulfoximine-treated GLC4/Sb30 cells was found to result in increased accumulation and reduced efflux of arsenic in cells exposed to As2O3, outlining the glutathione-dependence of MRP1-mediated transport of the metal. These results indicate that MRP1 overexpression in human tumor cells can confer resistance to As2O3, which may limit the clinical use of this anticancer drug for treatment of MRP1-positive tumors.

ATP-Binding Cassette Transporters↗
PubMed2001

Reactive oxygen species-related induction of multidrug resistance-associated protein 2 expression in primary hepatocytes exposed to sulforaphane.

Expression of multidrug resistance-associated protein 2 (MRP2), an efflux pump contributing to biliary secretion of xenobiotics, was investigated in primary rat and human hepatocytes exposed to sulforaphane, a naturally-occurring chemopreventive agent. Northern blot indicated that sulforaphane increased MRP2 mRNA levels in primary rat hepatocytes; it also induced expression of drug metabolizing enzymes such as glutathione S-transferase A1/2 isoforms and NAD(P)H:quinone oxidoreductase in a dose-response and time-course manner similar to that observed for the upregulation of MRP2 transcripts. This sulforaphane-related increase of MRP2 mRNAs paralleled increased expression of 190 kD MRP2 protein as assessed by Western blotting; it was fully abolished by the transcription inhibitor actinomycin D. MRP2 induction was associated with increased cellular production of reactive oxygen species (ROS) and addition of dimethyl sulfoxide, that reduced sulforaphane-related formation of ROS, and also decreased MRP2 mRNA levels in sulforaphane-treated primary rat hepatocytes; this suggests that sulforaphane-mediated production of ROS may contribute to MRP2 induction. This link between ROS and MRP2 regulation was further supported by the increase of MRP2 expression occurring in response to t-butylhydroquinone, known to regulate drug metabolizing enzymes through ROS formation. In addition to rat cells, primary human hepatocytes exposed to sulforaphane also displayed induced MRP2 expression evidenced at both mRNA and protein levels. All these observations strongly support the conclusion that the export pump MRP2 can be classified among the detoxifying proteins that are regulated by sulforaphane and that are thought to contribute, at least in part, to its anticarcinogenic properties.

Animals↗
PubMed2001

Unaltered expression of multidrug resistance transporters in polycyclic aromatic hydrocarbon-resistant rat liver cells.

Rat liver epithelial cells resistant to the chemical carcinogen 3MC, termed F258/3MC cells and generated by long-term exposure of parental F258 cells to the PAH, were characterized, especially with respect to expression of multidrug resistance transporters such as P-glycoprotein, MRP1 and MRP2. F258/3MC cells were found to be cross-resistant to other PAHs such as BP and dimethylbenz(a)anthracene but remained sensitive to known substrates of multidrug resistance efflux pumps such as doxorubicin and vincristine. They did not display either decreased cellular PAH accumulation or increased PAH efflux. In addition, P-glycoprotein and MRP2 mRNA levels were not, or only barely detected, in F258/3MC cells and in their parental counterparts whereas these PAH-resistant and sensitive cells showed closed levels of MRP1 mRNAs and activity. Moreover, P-gp- and MRP1-overexpressing cells were shown to display similar accumulation and efflux of BP than those found in P-gp- and MRP1-negative control cells. These data therefore suggest that multidrug resistance transporters do not contribute to PAH resistance in PAH-selected liver cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2001

Metabolism of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in human hepatocytes: 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic acid is a major detoxification pathway catalyzed by cytochrome P450 1A2.

Metabolic pathways of the mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) remain incompletely characterized in humans. In this study, the metabolism of MeIQx was investigated in primary human hepatocytes. Six metabolites were characterized by UV and mass spectroscopy. Novel metabolites were additionally characterized by 1H NMR spectroscopy. The carcinogenic metabolite, 2-(hydroxyamino)-3,8-dimethylimidazo[4,5-f]quinoxaline, which is formed by cytochrome P450 1A2 (P450 1A2), was found to be transformed into the N(2)-glucuronide conjugate, N(2)-(beta-1-glucosiduronyl)-2-(hydroxyamino)-3,8-dimethylimidazo[4,5-f]quinoxaline. The phase II conjugates N(2)-(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl)sulfamic acid and N(2)-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, as well as the 7-oxo derivatives of MeIQx and N-desmethyl-MeIQx, 2-amino-3,8-dimethyl-6-hydro-7H-imidazo[4,5-f]quinoxalin-7-one (7-oxo-MeIQx), and 2-amino-6-hydro-8-methyl-7H-imidazo[4,5-f]quinoxalin-7-one (N-desmethyl-7-oxo-MeIQx), thought to be formed exclusively by the intestinal flora, were also identified. A novel metabolite was characterized as 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic acid (IQx-8-COOH), and it was the predominant metabolite formed in hepatocytes exposed to MeIQx at levels approaching human exposure. IQx-8-COOH formation is catalyzed by P450 1A2. This metabolite is a detoxication product and does not induce umuC gene expression in Salmonella typhimurium strain NM2009. IQx-8-COOH is also the principal oxidation product of MeIQx excreted in human urine [Turesky, R., et al. (1998) Chem. Res. Toxicol. 11, 217-225]. Thus, P450 1A2 is involved in both the metabolic activation and detoxication of this procarcinogen in humans. Analogous metabolism experiments were conducted with hepatocytes of untreated rats and rats pretreated with the P450 inducer 3-methylcholanthrene. Unlike human hepatocytes, the rat cell preparations did not produce IQx-8-COOH but catalyzed the formation of 2-amino-3,8-dimethyl-5-hydroxyimidazo[4,5-f]quinoxaline as a major P450-mediated detoxication product. In conclusion, our results provide evidence of a novel MeIQx metabolism pathway in humans through P450 1A2-mediated C(8)-oxidation of MeIQx to form IQx-8-COOH. This biotransformation pathway has not been detected in experimental animal species. Considerable interspecies differences exist in the metabolism of MeIQx by P450s, which may affect the biological activity of this mutagen and must be considered when assessing human health risk.

Animals↗
PubMed2001

The sulphonylurea glibenclamide inhibits multidrug resistance protein (MRP1) activity in human lung cancer cells.

1. Glibenclamide, a sulphonylurea widely used for the treatment of non-insulin-dependent diabetes mellitus, has been shown to inhibit the activities of various ATP-binding cassette (ABC) transporters. In the present study, its effects towards multidrug resistance protein 1 (MRP1), an ABC efflux pump conferring multidrug resistance and handling organic anions, were investigated. 2. Intracellular accumulation of calcein, an anionic dye substrate for MRP1, was strongly increased by glibenclamide in a dose-dependent manner in MRP1-overexpressing lung tumour GLC4/Sb30 cells through inhibition of MRP1-related calcein efflux. By contrast, glibenclamide did not alter calcein levels in parental control GLC4 cells. Another sulphonylurea, tolbutamide, was however without effect on calcein accumulation in both GLC4/Sb30 and GLC4 cells. 3. Glibenclamide used at 12.5 microM was, moreover, found to strongly enhance the sensitivity of GLC4/Sb30 cells towards vincristine, an anticancer drug handled by MRP1. 4. Efflux of carboxy-2',7'-dichlorofluorescein, an anionic dye handled by the ABC transporter MRP2 sharing numerous substrates with MRP1 and expressed at high levels in liver, was also strongly inhibited by glibenclamide in isolated rat hepatocytes. 5. In summary, glibenclamide reversed MRP1-mediated drug resistance likely through inhibiting MRP1 activity and blocked organic anion efflux from MRP2-expressing hepatocytes. Such effects associated with the known inhibitory properties of glibenclamide towards various others ABC proteins suggest that this sulphonylurea is a general inhibitor of ABC transporters.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Carbamazepine: a 'blind' assessment of CVP-associated metabolism and interactions in human liver-derived in vitro systems.

1. The ability of various in vitro systems for CYP enzymes (computer modelling, human liver microsomes, precision-cut liver slices, hepatocytes in culture, recombinant enzymes) to predict various aspects of in vivo metabolism and kinetics of carbamazepine (CBZ) was investigated. 2. The study was part of the EUROCYP project that aimed to evaluate relevant human in vitro systems to study drug metabolism. 3. CBZ was given to the participating laboratories without disclosing its chemical nature. 4. The most important enzyme (CYP3A4) and metabolic route (10,11-epoxidation) were predicted by all the systems studied. 5. Minor enzymes and routes were predicted to a different extent by various systems. 6. Prediction of a clearance class, i.e. slow clearance, was correctly predicted by microsomes, slices, hepatocytes and recombinant enzymes (CYP3A4). 7. The 10,11-epoxidation of CBZ by the recombinant CYP3A4 was enhanced by the addition of exogenous cytochrome-b5, leading to a considerable over-prediction. 8. Induction potency of CBZ was predicted in cultured hepatocytes in which 7-ethoxycoumarin O-deethylase was used as an index activity. 9. It seems that for a principally CYP-metabolized substance such as CBZ, all liver-derived systems provide useful information for prediction of metabolic routes, rates and interactions.

Anticonvulsants↗
PubMed2001

Differential effects of oltipraz on CYP1A and CYP2B in rat lung.

Oltipraz (OPZ) is a potent chemopreventive agent against chemically-induced carcinogenesis in several animal models. It affects the expression and/or activity of xenobiotic-metabolizing enzymes and its effects are altered in the course of inflammation in liver. The present study was undertaken to analyse the effect of OPZ alone or in combination with Escherichia coli lipopolysaccharide (LPS) on the expression and activities of glutathione S-transferases (GSTs) and cytochrome P450 (CYPs) in rat lung and kidney. Male Wistar rats were fed a diet containing OPZ for 1-5 days. LPS was injected 24 h before the end of OPZ treatment (from 48 to 72 h). Total GST activity, measured using 1-chloro-2,4-dinitrobenzene as a substrate, increased slightly in both lung and kidney during OPZ treatment. As previously demonstrated in the liver, OPZ induced rat GSTP1 in both kidney and lung and this effect was totally (kidney) or partially (lung) inhibited by co-treatment with LPS. CYP1A expression and activity were strongly increased in both tissues 24 h after starting OPZ treatment and maintained for 5 days. This increase was suppressed during the acute-phase response to endotoxin. OPZ has no effect on CYP2B1 mRNA expression in the lung, but it dramatically decreased the amount and activity of the corresponding apoprotein. The OPZ-dependent decrease in the CYP2B1 apoprotein was abolished and its corresponding activity partially reversed during LPS treatment. In reconstitution experiments using cytosol from OPZ-treated or control rat lungs and microsomal fractions, CYP2B1 apoprotein was rapidly degraded in the presence of cytosol from treated rats. This effect was partially reversed in the presence of MG132, a proteasome inhibitor. These observations support the conclusion that the decrease of CYP2B1 by OPZ involves proteasome-dependent degradation and represents a new mechanism of regulation by this compound.

Animals↗
PubMed2001

Immunohistological analysis of glutathione transferase A4 distribution in several human tissues using a specific polyclonal antibody.

We examined the cellular distribution of glutathione transferase A4 (GSTA4) in various human tissues by indirect immunoperoxidase using a specific polyclonal antibody raised in rabbit. This enzyme was localized in hepatocytes, bile duct cells, and vascular endothelial cells in liver, upper layers of keratinocytes and sebaceous and sweat glands in skin, proximal convoluted tubules in kidney, epithelial cells of mucosa and muscle cells in colon, muscle cells in heart, and neurons in brain. Staining was increased in pathological situations such as cirrhosis, UV-irradiated skin, and myocardial infarction and was strongly decreased in hepatocellular carcinoma. These results strongly support the view of a close correlation between cellular GSTA4 localization and the formation of reactive oxygen species in the tissues investigated.

Animals↗
PubMed2001

An assessment of human liver-derived in vitro systems to predict the in vivo metabolism and clearance of almokalant.

The ability of various human derived in vitro systems to predict various aspects of the in vivo metabolism and kinetics of almokalant have been investigated in a multicenter collaborative study. Although almokalant has been withdrawn from further clinical development, its metabolic and pharmacokinetic properties have been well characterized. Studies with precision-cut liver slices, primary hepatocyte cultures, and hepatic microsomal fractions fortified with UDP-glucuronic acid all suggested that almokalant is mainly glucuronidated to the stereoisomers M18a and M18b, which is in good agreement with the results in vivo. Both in vivo and in vitro studies indicate that the formation of M18b dominates over that of M18a, although the difference is more pronounced with the in vitro systems. Molecular modeling, cDNA-expressed enzyme analysis, correlation analysis, and inhibition studies did not clearly indicate which P450 enzymes catalyze the oxidative pathways, which may indicate a problem in identifying responsible enzymes for minor metabolic routes by in vitro methods. All of the in vitro systems underpredicted the metabolic clearance of almokalant, which has previously been reported to be a general problem for drugs that are cleared by P450-dependent metabolism. Although few studies on in vivo prediction of primarily glucuronidated drugs have appeared, in vitro models may consistently underpredict in vivo metabolic clearance. We conclude that in vitro systems, which monitor phase II metabolism, would be beneficial for prediction of the in vivo metabolism, although all of the candidate liver-derived systems studied here, within their intrinsic limitations, provided useful information for predicting metabolic routes and rates.

Anti-Arrhythmia Agents↗
PubMed2001

Arsenic induces expression of the multidrug resistance-associated protein 2 (MRP2) gene in primary rat and human hepatocytes.

Metals, such as arsenic or cadmium, have recently been demonstrated to interact with metabolic pathways, including phase I and phase II enzymes and the phase III efflux pump P-glycoprotein. In the present study, we investigated the effects of heavy metals and metalloids on the expression of the multidrug resistance-associated protein 2 (MRP2), a major hepatic transporter. Treatment of primary rat hepatocytes by sodium arsenite [As(III)], sodium arsenate and potassium antimony tartrate, but not cadmium chloride, was shown to markedly increase MRP2 mRNA and protein levels; As(III)-mediated induction was dose- and time-dependent and paralleled a strong increase in MRP2 amounts as assessed by Western blotting. As(III) was also demonstrated to markedly up-regulate MRP2 gene expression in primary human hepatocytes. MRP2 mRNA induction occurring in As(III)-treated rat hepatocytes was fully blocked by actinomycin D, indicating that it required active gene transcription. It was associated with an activation of the c-Jun N-terminal kinase pathway and with a reduction of cellular glutathione levels. Quercetin, a flavonoid compound known to block As(III)-related induction of P-glycoprotein, was also found to prevent up-regulation of MRP2 gene expression in rat hepatocytes exposed to As(III). Such an effect was unlikely to be due to alteration of JNK pathway since quercetin failed to abolish As(III)-induced JNK phosphorylation. It may rather be linked to the increase of cellular glutathione levels by quercetin, thus limiting the depleting effects of As(III) on glutathione amounts. Finally, these results confirm that some metals strongly regulate expression of detoxifying proteins, including biliary drug transporters.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2001

Applications of biotechnology to pharmacology and toxicology.

Strategies for the development of new more efficient drugs at a lower cost and for the evaluation of the effects of chemicals and metals on tissue and cell function are changing considerably. This is made possible by recent progress in various areas, particularly biotechnology and bioinformatics. The recent sequencing of the human genome and the design of more and more sophisticated technologies will largely influence the fields of pharmacology and toxicology. Thus, identification of new molecular targets, development of more powerful cell models, design of miniaturized and automated tests for high throughput screening of thousands of compounds synthesized by combinatorial chemistry and progress in genomic and proteomic technologies that permit simultaneous analysis of thousands of genes and their products, offer new investigative ways that will still widely be extended in the next future.

Animals↗
PubMed2000

Characterization and inhibition by a wide range of xenobiotics of organic anion excretion by primary human hepatocytes.

Organic anion secretion by human hepatocytes was characterized using primary liver parenchymal cell cultures and the anionic fluorescent dye carboxy-2',7'-dichlorofluorescein (CF). Probenecid, a well-known common blocker of the membrane transport process for anions, was shown to increase CF accumulation in primary human hepatocytes by inhibiting cellular CF efflux in a dose-dependent manner, thereby establishing the presence of an efflux system for organic anions in cultured hepatocytes. Outwardly directed transport of CF from hepatocytes was found to be temperature-dependent; it was not altered by changes in the ionic composition of the incubation medium used in efflux experiments. In addition to probenecid, various structurally and functionally unrelated xenobiotics such as glibenclamide, rifampicin, vinblastine, MK-571, indomethacin, and cyclosporin A were shown to inhibit secretion of CF by primary human hepatocytes, thus suggesting that organic anion excretion by human liver may be impaired by various drugs. Northern blot and Western blot analyses of the expression of multidrug resistance proteins (MRP), such as MRP1 and MRP2, which are known to mediate cellular outwardly directed transport of organic anions indicated that MRP2 was present at substantial levels in cultured human hepatocytes as well as in their in vivo counterparts, whereas MRP1 expression was only barely detectable. These results therefore suggest that MRP2, unlike MRP1, may contribute to the organic anion efflux system displayed by primary human hepatocytes and inhibited by a wide range of xenobiotics.

Anion Transport Proteins↗
PubMed2000

Expression and regulation of hepatic drug and bile acid transporters.

Transport across hepatocyte plasma membranes is a key parameter in hepatic clearance and usually occurs through different carrier-mediated systems. Sinusoidal uptake of compounds is thus mediated by distinct transporters, such as Na(+)-dependent or Na(+)-independent anionic transporters and by some cationic transporters. Similarly, several membrane proteins located at the apical pole of hepatocytes have been incriminated in the excretion of compounds into the bile. Indeed, biliary elimination of anionic compounds, including glutathione S-conjugates, is mediated by MRP2, whereas bile salts are excreted by a bile salt export pump (BSEP) and Class I-P-glycoprotein (P-gp) is involved in the secretion of amphiphilic cationic drugs, whereas class II-P-gp is a phospholipid transporter. The expression of hepatic transporters and their activity are regulated in various situations, such as ontogenesis, carcinogenesis, cholestasis, cellular stress and after treatment by hormones and xenobiotics. Moreover, a direct correlation between a defect and the absence of transporter with hepatic disease has been demonstrated for BSEP, MDR3-P-gp and MRP2.

Animals↗
PubMed2000

Inhalation of toluene diisocyanate affects cytochrome P450 2B1 expression in rat lung.

In the lung the expression of xenobiotic-metabolizing enzymes such as cytochromes P450 (CYP) and glutathione S-transferases (GST) may be affected by inhaled pollutants. Toluene diisocyanate (TDI) is a highly volatile chemical compound known to induce a wide array of diseases in workers exposed to vapors or sprays, including respiratory allergy and asthma. We investigated the effect of inhaled TDI on expression of CYP 1A1, 2B1, 2E1, and 3A1 and of alpha-, mu-, and pi-GST in rat lung. Animals were exposed to targeted concentrations of 0.01, 0.1, or 1 ppm TDI vapors or to cleaned filtered air for 8 h. Expression of CYP and GST was analyzed 18 24 h after the end of exposure using western blotting, northern blotting, and immunohistochemistry. Constitutive levels of CYP 2B1 and 3A1 proteins were found in lung tissue from control rats, whereas CYP 1A1 and 2E1 proteins were not detectable. Animal exposure to TDI vapors neither modified CYP 3A1 protein expression, nor led to any detectable expression of CYP 1A1 or 2E1. In contrast, exposure to 1 ppm TDI induced a 40% reduction in CYP 2B1 protein levels. This decrease was associated with a 33% decrease in CYP 2B1 mRNA levels. Additionally, CYP 2B1 immunolabeling localized to ciliated epithelial cells, Clara cells, and type II alveolar cells in the lung tissue of control rats was markedly decreased in animals exposed to 1 ppm TDI. Constitutive levels of alpha-, mu-, and pi-GST proteins were found in lung tissue from control rats. Exposure to TDI had no effect on lung expression of either of the GST. In conclusion, this study clearly shows a selective decrease in CYP 2B1 expression by TDI vapors in rat lung. The contribution of CYP 2B1 to metabolize further xenobiotics is therefore altered.

Administration, Inhalation↗
PubMed2000

Inhibition of human cytochrome P450 enzymes by 1,2-dithiole-3-thione, oltipraz and its derivatives, and sulforaphane.

Recent studies have demonstrated that two chemoprotective agents, oltipraz (OPZ), a synthetic derivative of the natural compound 1, 2-dithiole-3-thione (D3T), and sulforaphane (SF), an isothiocyanate, are not only inducers of glutathione S-transferases but also inhibitors of some major cytochrome P450 enzymes (P450s) involved in xenobiotic metabolism. We examined P450 inhibition by the two compounds and compared two OPZ metabolites (OPZ M(3) and M(8)) and D3T using human P450s expressed in Escherichia coli membranes. OPZ was a more potent inhibitor than D3T or SF, in the following order of inhibition: P450 1A2 > 3A4 > 1A1 approximately 1B1 > 2E1. OPZ M(3) also inhibited P450s 1A2, 1A1, 1B1, and 3A4 but not more effectively than OPZ. OPZ M(8) was not inhibitory. OPZ behaved as a competitive inhibitor of P450 1A2, with a K(i) of 1.5 microM. Incubation of P450 1A2 with OPZ and NADPH led to a first-order loss of the P450 spectrum, and the loss was not blocked by glutathione. No such time-dependent loss of P450 was seen with P450 1A2 and D3T, P450 1A2 and OPZ M(3), P450 1A2 and SF, P450 3A4 and OPZ, P450 3A4 and D3T, P450 2E1 and OPZ, or P450 2E1 and D3T. The time- and concentration-dependent loss of P450 1A2 activity in the presence of OPZ was characterized with a K(i) of 9 microM and a k(inactivation) of 0.19 min(-)(1). The activation of 2-amino-3,5-dimethylimidazo[4, 5-f]quinoline (MeIQ) in an E. coli lac-based mutagenicity tester system containing functional human P450 1A2 was inhibited by OPZ (IC(50) < 1 microM) but not appreciably by 40 microM D3T. Our results indicate that OPZ is a competitive and mechanism-based inhibitor of P450 1A2, and the extent of this inhibition is significantly greater than that of other chemoprotective chemicals with P450 1A2 or other human P450s.

Anticarcinogenic Agents↗