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Biochemical Pharmacology (v.75, #8)

Editorial Advisory Board (pp. ii).

Anti-inflammatory interventions of NF-κB signaling: Potential applications and risks by Senftleben Uwe (pp. 1567-1579).

Signaling via NF-κB is a key process during inflammation and thus constitutes an attractive target for anti-inflammatory therapeutic interventions. Especially during initial hyperinflammatory states of an acute illness such as sepsis or in the course of chronic inflammation and autoimmune diseases inhibition of IKK-driven NF-κB activation provides a promising treatment strategy. Given its critical role in innate and adaptive immune responses, however, there is a certain amount of risk due to induced immunodeficiency that may follow inhibitory treatment. Moreover, its primary anti-apoptotic function suggests that blockade of NF-κB activation has dramatic effects on cell functions and survival and eventually worsens the course of an inflammatory disease.An overview of canonical and alternative NF-κB activation and its critical role in immune responses will be provided. A main topic focuses on recent animal studies and data derived from genetic studies in humans that provide an insight into potential effects of different therapeutic modulations of NF-κB inflammatory signaling. The pros and cons of NF-κB inhibition and treatment strategies will be critically reviewed.

Keywords: NF-κB; Inflammation; Apoptosis; Immunosuppression; Signaling

Accumulation of the antimalarial microtubule inhibitors trifluralin and vinblastine by Plasmodium falciparum by Julie Ann Naughton; Ruth Hughes; Patrick Bray; Angus Bell (pp. 1580-1587).

Malaria is a disease in desperate need of new chemotherapeutic approaches. Certain microtubule inhibitors, including vinblastine and taxol, have highly potent activity against malarial parasites and disrupt the normal microtubular structures of intra-erythrocytic parasites at relevant concentrations. While these inhibitors are useful tools, their potential as anti-malarial drugs is limited by their high toxicity to mammalian cells. In contrast, two classes of antimitotic herbicide, namely dinitroanilines (e.g. trifluralin and oryzalin) and phosphorothioamidates (e.g. amiprophosmethyl), exhibit moderate activity against the major human malarial parasite Plasmodium falciparum in culture but very low mammalian cytotoxicity. We examined the dynamics and kinetics of uptake and subcellular compartmentation of [¹⁴C]trifluralin in comparison with [³H]vinblastine. We wished to determine whether the relatively modest activity of trifluralin was the consequence of poor uptake into parasite cells. Trifluralin accumulated in parasite-infected erythrocytes to ∼300 times the external concentration and vinblastine at up to ∼110 times. Accumulation into uninfected erythrocytes was much lower. Uptake of trifluralin was rapid, non-saturable and readily reversed. It appears that the hydrophobic nature of trifluralin leads to accumulation largely in the membranes of the parasite, reducing the levels in the soluble fraction and limiting access to its microtubular target. By contrast, vinblastine accumulated predominantly in the soluble fraction and uptake was saturable and mostly irreversible, consistent with binding predominantly to tubulin. The results indicate that synthesis of more polar trifluralin derivatives may be a promising approach to designing microtubule inhibitors with more potent antimalarial activity.

Keywords: Malaria; Trifluralin; Vinblastine; Accumulation; Microtubules

Structure–activity relationship for adenosine kinase from Mycobacterium tuberculosis by Mary C. Long; Sue C. Shaddix; Omar Moukha-Chafiq; Joseph A. Maddry; Lisa Nagy; William B. Parker (pp. 1588-1600).

Adenosine kinase (Ado kinase) from Mycobacterium tuberculosis is structurally and biochemically unique from other known Ado kinases. This purine salvage enzyme catalyzes the first step in the conversion of the adenosine analog, 2-methyl-Ado (methyl-Ado), into a metabolite with antitubercular activity. Methyl-Ado has provided proof of concept that the purine salvage pathway from M. tuberculosis may be utilized for the development of antitubercular compounds with novel mechanisms of action. In order to utilize this enzyme, it is necessary to understand the topography of the active site to rationally design compounds that are more potent and selective substrates for Ado kinase. A previous structure–activity relationship identified modifications to the base moiety of adenosine (Ado) that result in substrate and inhibitor activity. In an extension of that work, 62 Ado analogs with modifications to the ribofuranosyl moiety, modifications to the base and ribofuranosyl moiety, or modifications to the glycosidic bond position have been analyzed as substrates and inhibitors of M. tuberculosis Ado kinase. A subset of these compounds was further analyzed in human Ado kinase for the sake of comparison. Although no modifications to the ribose moiety resulted in compounds as active as Ado, the best substrates identified were carbocyclic-Ado, 8-aza-carbocyclic-Ado, and 9-[α-l-lyxofuranosyl]-adenine with 38%, 4.3%, and 3.8% of the activity of Ado, respectively. The most potent inhibitor identified, 5′-amino-5′-deoxy-Ado, had a K_i=0.8μM and a competitive mode of inhibition. MIC studies demonstrated that poor substrates could still have potent antitubercular activity.

Keywords: Abbreviations; Ade; adenine; Ado; adenosine; AD; adenosine deaminase; araA; 9-[β-; d; -arabinofuranosyl]-adenine; AMP-PCP; adenosine 5′-(β,γ-methylene)triphosphate; BSA; bovine serum albumin; DTT; dithiothreitol; formycin A; 8-aza-9-deaza-Ado; IPTG; isopropyl-β-; d; -thiogalactopyranoside; methyl-Ado; 2-methyl-adenosine; MTAP; methylthioadenosine phosphorylase; MIC; 95% minimum inhibitory concentration; PBS; phosphate buffered saline; P; _i; inorganic phosphate; PMSF; phenylmethylsulfonyl fluoride; SAR; structure–activity relationshipAdenosine kinase; Mycobacterium tuberculosis; Nucleoside analog; Structure–activity relationship; Ribose

Thiopurine analogues inhibit papain-like protease of severe acute respiratory syndrome coronavirus by Chi-Yuan Chou; Chia-Hui Chien; Yu-San Han; Mojca Trstenjak Prebanda; Hsing-Pang Hsieh; Boris Turk; Gu-Gang Chang; Xin Chen (pp. 1601-1609).

The papain-like protease of severe acute respiratory syndrome coronavirus (PLpro) (EC 3.4.22.46) is essential for the viral life cycle and therefore represents an important antiviral target. We have identified 6MP and 6TG as reversible and slow-binding inhibitors of SARS-CoV PLpro, which is the first report about small molecule reversible inhibitors of PLpro. The inhibition mechanism was investigated by kinetic measurements and computer docking. Both compounds are competitive, selective, and reversible inhibitors of the PLpro with K_is values ∼10 to 20μM. A structure–function relationship study has identified the thiocarbonyl moiety of 6MP or 6TG as the active pharmacophore essential for these inhibitions, which has not been reported before. The inhibition is selective because these compounds do not exert significant inhibitory effects against other cysteine proteases, including SARS-CoV 3CLpro and several cathepsins. Thus, our results present the first potential chemical leads against SARS-CoV PLpro, which might be used as lead compounds for further optimization to enhance their potency against SARS-CoV. Both 6MP and 6TG are still used extensively in clinics, especially for children with acute lymphoblastic or myeloblastic leukemia. In light of the possible inhibition against subset of cysteine proteases, our study has emphasized the importance to study in depth these drug actions in vivo.

Keywords: Abbreviations; SARS; severe acute respiratory syndrome; CoV; coronavirus; PLpro; papain-like proteinase 2; 3CLpro; 3-chymotrypsin-like protease; DUB; deubiquitination enzyme; AMC; 7-amino-4-methylcoumarin; FRET; fluorescence resonance energy transfer; 6MP; 6-mercaptopurine; 6TG; 6-thioguanineSevere acute respiratory syndrome coronavirus; Papain-like proteinase 2; Inhibitor; 6-Mercaptopurine; 6-Thioguanine; Cysteine protease

Effect of AZT on thymidine phosphorylation in cultured H9c2, U-937, and Raji cell lines by Matthew D. Lynx; Bae-Kwang Kang; Edward E. McKee (pp. 1610-1615).

3′-Azido-3′-deoxythymidine (AZT) has been shown to be a potent inhibitor of thymidine kinase 2 in work from this laboratory. Inhibition results in decreased salvage of thymidine to TTP, which may lead to depletion of the TTP pool and result in the mitochondrial dysfunction and mt-DNA depletion observed with AZT toxicity. The effect of AZT on thymidine phosphorylation in growing cells expressing thymidine kinase 1 has not been shown. Three cell lines were used in these experiments: H9c2, derived from rat cardiomyoblasts; U-937, derived from human monocytes; and Raji, derived from human lymphoblasts. AZT inhibited growth in a concentration-dependent manner in U-937 cells, but not the other cell lines. The phosphorylation of [³H]-thymidine or [³H]-AZT was determined during log growth. All cell lines salvaged and phosphorylated thymidine to TTP, with TTP the major product. The U-937 cells had a much more active salvage pathway than the other cells. All cell lines phosphorylated AZT to the triphosphate, but the major product was AZTMP. The AZT inhibition of growth of the U-937 cells did not correlate with levels of the phosphorylated AZT. In contrast, pro-drug AZT was shown to inhibit thymidine phosphorylation in all lines with 50% inhibition concentrations (IC₅₀) ranging from 4.4 to 21.9μM. Since the U-937 cells expressed higher activity of the salvage pathway than the other cell lines, the U-937 cells may rely more heavily on the salvage pathway for TTP synthesis, accounting for AZT inhibition of growth.

Keywords: AZT; Thymidine; Mitochondrial toxicity; Reverse transcriptase inhibitors; Cultured cells

Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes: A possible mechanism of chemotherapy-induced circadian rhythm disturbances by Hideyuki Terazono; Ahmed Hamdan; Naoya Matsunaga; Naoto Hayasaka; Hiroaki Kaji; Takashi Egawa; Kazutaka Makino; Yasufumi Shigeyoshi; Satoru Koyanagi; Shigehiro Ohdo (pp. 1616-1622).

The circadian clock system is necessary to adapt endogenous physiological functions to daily variations in environmental conditions. Abnormality in circadian rhythms, such as the sleep–wake cycle and the timing of hormonal secretions, is implicated in various physiological and psychiatrical disorders. Recent molecular studies have revealed that oscillation in the transcription of specific clock genes plays a central role in the generation of 24h cycles of physiology and behavior. It has been noticed that patients receiving chemotherapeutic agents experience disturbances in their behavioral and physical performances, including circadian rhythms. To explore the underlying mechanism of chemotherapeutic agent-induced disturbance of these rhythms, we investigated the influence of 5-fluorouracil (5-FU), one of the most widely used chemotherapeutic agents for the treatment of cancers, on the expression of clock genes. Treatment of cultured NIH3T3 cells with 5-FU for 48h resulted in a significant reduction of mRNA levels of Period1 ( Per1) and Period2 ( Per2) without affecting cell viability; however, treatment with the same amount of uracil, a structural analog of 5-FU, had little effect on the expression of clock genes. Consistent with its inhibitory actions, continuous administration of 5-FU (2mg/kg/h) to mice attenuated the oscillation in the expressions of Per1 and Per2 in the liver and suprachiasmatic nuclei, the center of the mammalian circadian clock. These results reveal a possible pharmacological action by the chemotherapeutic agent 5-FU on the circadian clock mechanism, which is the underlying cause of its adverse effects on 24-h rhythms of physiology and behavior.

Keywords: Abbreviations; 5-FU; 5-fluorouracil; ATP; adenosine triphosphate; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; SCN; suprachiasmatic nucleusChemotherapy; 5-Fluorouracil; Circadian rhythm; Clock genes; Suprachiasmatic nuclei

Transactivation of epidermal growth factor receptor in vascular and renal systems in rats with experimental hyperleptinemia: Role in leptin-induced hypertension by Anna Jamroz-Wiśniewska; Grażyna Wójcicka; Ewelina Łowicka; Marta Książek; Jerzy Bełtowski (pp. 1623-1638).

We examined the role of epidermal growth factor (EGF) receptor in the pathogenesis of leptin-induced hypertension in the rat. Leptin, administered in increasing doses (0.1–0.5mg/kg/day) for 10 days, increased phosphorylation levels of non-receptor tyrosine kinase, c-Src, EGF receptor and extracellular signal-regulated kinases (ERK) in aorta and kidney, which was accompanied by the increase in plasma concentration and urinary excretion of isoprostanes and H₂O₂. Blood pressure and renal Na⁺,K⁺-ATPase activity were higher, whereas urinary sodium excretion was lower in animals receiving leptin. The effects of leptin on renal Na⁺,K⁺-ATPase, natriuresis and blood pressure were abolished by NADPH oxidase inhibitor, apocynin, Src kinase inhibitor, PP2, EGF receptor inhibitor, AG1478, protein farnesyltransferase inhibitor, manumycin A, and ERK inhibitor, PD98059. In contrast, inhibitors of insulin-like growth factor-1 and platelet-derived growth factor receptors, AG1024 and AG1295, respectively, only slightly reduced ERK phosphorylation and had no effect on blood pressure in rats receiving leptin. These data indicate that: (1) experimental hyperleptinemia is associated with oxidative stress and c-Src-dependent transactivation of the EGF receptor, which stimulates ERK in vascular wall and the kidney, (2) overactivity of EGF receptor-ERK pathway contributes to leptin-induced hypertension by stimulating renal Na⁺,K⁺-ATPase and reducing sodium excretion, (3) inhibitors of c-Src, EGF receptor and ERK may be considered as a novel therapy for hypertension associated with hyperleptinemia, e.g. in patients with obesity and metabolic syndrome.

Keywords: Leptin; Arterial hypertension; Epidermal growth factor receptor; Extracellular signal-regulated kinases; c-Src tyrosine kinase; Na; ⁺; ,K; ⁺; -ATPase

Domain mapping of a claudin-4 modulator, the C-terminal region of C-terminal fragment of Clostridium perfringens enterotoxin, by site-directed mutagenesis by Azusa Takahashi; Eriko Komiya; Hideki Kakutani; Takeshi Yoshida; Makiko Fujii; Yasuhiko Horiguchi; Hiroyuki Mizuguchi; Yasuo Tsutsumi; Shin-ichi Tsunoda; Naoya Koizumi; Katsuhiro Isoda; Kiyohito Yagi; Yoshiteru Watanabe; Masuo Kondoh (pp. 1639-1648).

A C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) is a modulator of claudin-4. We previously found that upon deletion of the C-terminal 16 amino acids, C-CPE lost its ability to modulate claudin-4. Tyrosine residues in the 16 amino acids were involved in the modulation of claudin-4. In the present study, we performed functional domain mapping of the 16-amino acid region of C-CPE by replacing individual amino acids with alanine. To evaluate the ability of the alanine-substituted mutants to interact with claudin-4, we carried out a competition analysis using claudin-4-targeting protein synthesis inhibitory factor. We found that Tyr306Ala, Tyr310Ala, Tyr312Ala, and Leu315Ala mutants had reduced binding to claudin-4 compared to C-CPE. Next, we investigated effects of each alanine-substituted mutant on the TJ-barrier function in Caco-2 monolayer cells. The TJ-disrupting activity of C-CPE was reduced by the Tyr306Ala and Leu315Ala substitutions. Enhancement of rat jejunal absorption was also decreased by each of these mutations. The double mutant Tyr306Ala/Leu315Ala lost the ability to interact with claudin-4, modulate TJ-barrier function, and enhance jejunal absorption. These data indicate that Tyr306 and Leu315 are key residues in the modulation of claudin-4 by C-CPE. This information should be useful for the development of a novel claudin modulator based on C-CPE.

Keywords: Abbreviations; TJ; tight junction; C-CPE; C-terminal fragment of; Clostridium perfringens; enterotoxin; CPE; Clostridium perfringens; enterotoxin; SDS-PAGE; sodium dodecyl sulfate-polyacrylamide gel electrophoresis; C-CPE-PSIF; C-CPE-fused protein synthesis inhibitory factor; LDH; lactate dehydrogenase; TEER; transepithelial electric resistance; FD-4; fluorescein isothiocyanate-dextran with a molecular weight of 4000 Clostridium perfringens; enterotoxin; Tight junction; Claudin; Site-directed mutagenesis

Insulin therapy restores impaired function and expression of P-glycoprotein in blood–brain barrier of experimental diabetes by Haiyan Liu; Xiaodong Liu; Lee Jia; Yuchun Liu; Huiwen Yang; Guangji Wang; Lin Xie (pp. 1649-1658).

We aimed to investigate effects of insulin on function and expression of P-glycoprotein (P-GP) in the blood–brain barrier of streptozotocin (STZ)-induced diabetic rats. Brain-to-plasma concentration ratio of vincristine (VCR) in rats was used as an indicator of in vivo function of P-GP. Western blot and quantitative real time-polymerase chain reaction were used to determine protein levels of P-GP and its mdr1a/ mdr1b mRNA levels, respectively, in cerebral cortex of rats. In vitro effects of insulin on function and expression of P-GP in primarily cultured rat brain microvessel endothelial cells (rBMECs) were evaluated using rhodamine 123 (Rho123) uptakes and Western blot, respectively. The results showed that 3- and 5-week insulin treatment alleviated the impaired efflux function, expression and mdr1a/ mdr1b mRNA levels of P-GP in cerebral cortex of diabetic rats. The 3- and 5-week insulin treatments also significantly enhanced P-GP levels and mdr1a/ mdr1b mRNA levels in the cerebral cortex of normal rats. Addition of insulin to the insulin-deficient diabetic rat serum normalized the impaired function and expression of P-GP in rBMECs cultured in diabetic rat serum. When incubated with normal culture medium containing different levels of insulin, the rBMECs exhibited the enhanced P-GP levels and the reduced Rho123 uptake in a concentration-dependent manner. So we may conclude that appropriate level of insulin plays an important role in maintaining the normal function of BBB through regulating the function and expression of P-GP in the diabetic and normal rats.

Keywords: Abbreviations; AGEs; advanced glycation end-products; BBB; blood–brain barrier; DM; diabetes mellitus; FBG; fasting blood glucose; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; HBSS; Hank's balance salt solution; MDR; multidrug resistance; P-GP; P-glycoprotein; Q-PCR; quantitative real time-polymerase chain reaction; rBMEC; rat brain microvessel endothelial cells; Rho123; rhodamine 123; STZ; streptozotocin; VCR; vincristineBlood–brain barrier; Insulin; P-glycoprotein; Diabetes mellitus; mdr1a; /; mdr1b; mRNA

Role of proline 1150 in functional interactions between the membrane spanning domains and nucleotide binding domains of the MRP1 (ABCC1) transporter by Isabelle J. Létourneau; Akio Nakajima; Roger G. Deeley; Susan P.C. Cole (pp. 1659-1669).

The ATP-binding cassette multidrug resistance protein 1 (MRP1) mediates ATP-dependent cellular efflux of drugs and organic anions. We previously described a mutant, MRP1-Pro1150Ala, which exhibits selectively increased estradiol glucuronide (E₂17βG) and methotrexate transport as well as altered interactions with ATP. We have now further explored the functional importance of MRP1-Pro¹¹⁵⁰ at the interface of transmembrane helix 15 and cytoplasmic loop 7 (CL7) by replacing it with Gly, Ile, Leu and Val. All four mutants exhibited a phenotype similar to MRP1-Pro1150Ala with respect to organic anion transport and [γ³²P]8N₃ATP photolabeling. They also displayed very low levels of substrate-independent vanadate-induced trapping of [α³²P]8N₃ADP. To better understand the relationship between the altered nucleotide interactions and transport activity of these mutants, [α³²P]8N₃ADP trapping experiments were performed under different conditions. Unlike leukotriene C₄, E₂17βG decreased [α³²P]8N₃ADP trapping by both wild-type and mutant MRP1. [α³²P]8N₃ADP trapping by MRP1-Pro1150Ala could be increased by using Ni²⁺ instead of Mg²⁺, and by decreasing temperature; however, the transport properties of the mutant remained unchanged. We conclude that the reduced [α³²P]8N₃ADP trapping associated with loss of Pro¹¹⁵⁰, or the presence of E₂17βG, is due to enhanced ADP release following ATP hydrolysis rather than a reduction in ATP hydrolysis itself. We hypothesize that loss of Pro¹¹⁵⁰ alters the role of CL7 as a coupling helix that mediates signaling between the nucleotide binding domains and some substrate binding sites in the membrane spanning domains of MRP1.

Keywords: Abbreviations; MRP; multidrug resistance protein; ABC; ATP-binding cassette; MSD; membrane spanning domain; NBD; nucleotide binding domain; LTC; ₄; leukotriene C; ₄; E; ₂; 17βG; 17β-estradiol 17β-; d; -glucuronide; CL; cytoplasmic loop; MTX; methotrexate; HEK; human embryonic kidney; TM; transmembrane; TSB; Tris–sucrose buffer; MAb; monoclonal antibodyMRP1; Organic anion transport; ATP-binding and hydrolysis; Active transport; ATP-binding cassette

Quercetin pretreatment increases the bioavailability of pioglitazone in rats: Involvement of CYP3A inhibition by Sudhir N. Umathe; Pankaj V. Dixit; Vijendra kumar; Kuldeep U. Bansod; Manish M. Wanjari (pp. 1670-1676).

Herbal antidiabetic preparations are often used as an add-on therapy in diabetes and such herbal preparations often contains quercetin that can inhibit cytochrome P450 (CYP) 3A4. This enzyme is responsible for metabolizing pioglitazone, a commonly used antidiabetic agent. Hence, it was speculated that quercetin may influence the bioavailability of pioglitazone, which could be particularly crucial, as any increment in its plasma levels may raise safety concerns. Thus, we first established the inhibitory influence of quercetin (2, 10 and 20mg/kg, p.o.) on CYP3A activity by an in vivo method of estimating levels of midazolam in female rats pretreated with dexamethasone. It was further confirmed in vitro using erythromycin- N-demethylase (EMD) assay. These studies indicated potent inhibition of CYP3A activity by quercetin (10 and 20mg/kg, in vivo; 1 and 10μM, in vitro). In another experiment, pioglitazone was administered orally (10mg/kg) and intravenously (5mg/kg) to quercetin (10mg/kg) pretreated female rats and its plasma levels were determined at various time points (0.5, 1, 2, 4, 8 and 24h after oral administration; 0.083, 0.5, 1, 2, 8, 12 and 18h after i.v. administration) by HPLC. Quercetin pretreatment increased AUC_0–∞ of pioglitazone after oral administration by 75% and AUC_0–∞ after intravenous administration by 25% suggesting decreased metabolism, which could be due to inhibition of CYP3A by quercetin. In conclusion, add-on preparations containing quercetin may increase the bioavailability of pioglitazone, and hence should be cautiously used.

Keywords: Cytochrome P450 3A (CYP3A); Herb–drug interactions; Diabetes mellitus; Pharmacokinetics; HPLC

Changes in maternal liver Cyp2c and Cyp2d expression and activity during rat pregnancy by Leslie J. Dickmann; Suzanne Tay; Tauri D. Senn; Huixia Zhang; Anthony Visone; Jashvant D. Unadkat; Mary F. Hebert; Nina Isoherranen (pp. 1677-1687).

During human pregnancy, CYP2C9, CYP2C19, and CYP2D6 activities are altered. The aim of the current study was to determine if this phenomenon can be replicated in the rat, and to evaluate the mechanisms that contribute to the changes in Cyp2c and Cyp2d activity during pregnancy. The intrinsic clearance of dextromethorphan O-demethylation, a measure of Cyp2d2 activity, was decreased 80% at both days 9 and 19 of gestation when compared to non-pregnant controls. The decreased intrinsic clearance was a result of both decreased V_max and increased K_m-values at both days of gestation. Quantitative RT-PCR revealed that transcripts of Cyp2d2 and Cyp2d4 were significantly decreased at day 19 of pregnancy ( p<0.05) when compared to day 9 and non-pregnant controls. The decrease in Cyp2d mRNA levels correlated with a decrease in several nuclear receptor mRNA levels (RARα, RXRα, HNF1 and HNF3β) but not with the mRNA levels of nuclear receptors usually associated with regulation of P450 enzymes (PXR, CAR and HNF4α). In contrast, Cyp2c12 and Cyp2c6 transcription and protein expression were not significantly altered during rat pregnancy although the intrinsic clearance of Cyp2c6 mediated diclofenac 4′-hydroxylation was increased 2-fold on day 19 of gestation when compared to non-pregnant controls. The increase in intrinsic clearance was due to a decrease in the K_m-value for 4′-hydroxydiclofenac formation. These data show that pregnancy significantly alters the expression and activity of drug metabolizing enzymes in an enzyme and gestational stage specific manner. These changes are likely to have toxicological and therapeutic implications.

Keywords: Abbreviations; RT-PCR; real time PCR; RAR; retinoic acid receptor; RXR; retinoid X receptor; HNF; hepatic nuclear factor; PXR; pregnane X receptor; CAR; constitutive androstane receptor; PBS; phosphate buffered saline; TE; tris-EDTAJEL classification; (8) Pharmacokinetics; Drug metabolismLiver; Cyp2c; Cyp2d; Pregnancy; Metabolism

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Biochemical Pharmacology (v.75, #8)