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Biochemical Pharmacology (v.72, #3)

Editorial Advisory Board (pp. iii).

Regulating the regulator: Factors that control levels and activity of the aryl hydrocarbon receptor by Patricia A. Harper; David S. Riddick; Allan B. Okey (pp. 267-279).

The aryl hydrocarbon receptor (AHR) participates in a wide range of critical cellular events in response to endogenous signals or xenobiotic chemicals. Hence, it is important that AHR levels and activity themselves be well controlled in target tissues. The AHR is essentially ubiquitous in its distribution in mammalian tissues. However, levels of the receptor vary widely across different tissues and among different cell types. AHR levels and activity are modulated by exposure to the receptor's own ligands and are influenced by other xenobiotic chemicals. Many different factors impinge on AHR levels and AHR activity. These factors may alter responsiveness of downstream pathways, thereby affecting normal physiologic functions as well as responses to toxic environmental chemicals such as dioxins. Our commentary appraises the current literature on factors that regulate AHR levels/activity and attempts to identify fruitful strategies towards discovery of key pathways by which AHR levels are modulated in response to endogenous signals and in response to xenobiotic chemicals. An extraordinarily large number of agents alter the level or activity of the AHR. We have not yet entered an age of enlightenment sufficient to achieve true understanding of the interplay of mechanisms that regulate AHR expression in space and in time.

Keywords: Abbreviations; AHR; aryl hydrocarbon receptor; AHRE; AH response element (also known as DRE or XRE); AHRR; aryl hydrocarbon receptor repressor; ARNT; aryl hydrocarbon receptor nuclear translocator; B[; a; ]P; benzo[; a; ]pyrene; E2; 17β-estradiol; ER; estrogen receptor; HNF; hepatic nuclear factor; IL-4; interleukin-4; MC; 3-methylcholanthrene; PAH; polycyclic aromatic hydrocarbon; PCB; polychlorinated biphenyl; TCDD; 2,3,7,8-tetrachlorodibenzo-; p; -dioxin; TCPOBOP; 1,4-bis[2-(3,5-dichloropyridyloxy)]benzeneAryl hydrocarbon receptor; AH receptor; Dioxin; 2,3,7,8-Tetrachlorodibenzo-; p; -dioxin; TCDD; Expression

Differential processing of antitumour-active and antitumour-inactive trans platinum compounds by SKOV-3 ovarian cancer cells by Angelina Boccarelli; Domenico Giordano; Giovanni Natile; Mauro Coluccia (pp. 280-292).

In order to compare the mechanistic properties of the antitumour-active trans platinum complex trans-[PtCl₂{ Z-HN=C(OMe)Me}(NH₃)] ( trans- Z) and of the antitumour-inactive isomer of cisplatin trans-[PtCl₂(NH₃)₂] ( trans-DDP), the differential processing of the two compounds by SKOV-3 ovarian cancer cells has been investigated. trans- Z and trans-DDP enter cells with the same efficacy, but trans- Z shows a two-fold higher affinity for cellular DNA. The treatment with trans-DDP IC₅₀ determines an initial and transient cytostatic effect, paralleled by a moderate increase of apoptosis and by sequential and reversible arrests in S and G₂/M phases of cell-cycle. In contrast, trans- Z IC₅₀ determines an initial cytotoxic effect, a more persistent and marked increase of apoptosis, and a more marked and prolonged arrest in S and G₂/M phases of the cell-cycle. Treatment-induced gene expression modifications indicate that phenotypic effects of trans-DDP are driven by an initial and transient up-regulation of some genes related to cell-cycle checkpoint and arrest networks, whereas the more dramatic phenotypic effects of trans- Z are driven by a persistent up-regulation of more numerous genes involved in cell-cycle checkpoint and arrest networks, and in genome stability and DNA repair. Therefore, molecular and cellular events have been identified which are produced by trans- Z but not by trans-DDP, and which likely represent the mechanistic basis of antitumour activity of trans- Z in the SKOV-3 system.

Keywords: Platinum anticancer drugs; Trans; geometry; Iminoether, SKOV-3 tumour cells; Cell-cycle; Gene expression

P-glycoprotein enhances TRAIL-triggered apoptosis in multidrug resistant cancer cells by interacting with the death receptor DR5 by Soo-Jung Park; Ching-Huang Wu; Mi-Ran Choi; Farhad Najafi; Armaghan Emami; Ahmad R. Safa (pp. 293-307).

The death-inducing cytokine TRAIL is a promising agent for anticancer therapy since it preferentially kills cancer versus normal cells; however, some cancer cells are TRAIL-resistant. We initially explored whether overexpression of the MDR1 gene product P-glycoprotein (P-gp), which causes multidrug resistance (MDR) in cancer cells, also contributes to TRAIL-resistance. Surprisingly, our results revealed that P-gp-overexpression enhances TRAIL-induced apoptosis not only in neoplastic cells transfected with the MDR1 gene but also in MDR variants selected with cytotoxic anticancer agents. Mechanistic analysis of TRAIL-induced apoptosis in the MDR1-transfected MCF-7 breast cancer cell line BC-19 revealed that TRAIL-triggered significantly more apoptosis in these cells compared with parental MCF-7 cells by binding to the TRAIL receptor DR5. DR5 but not DR4 engagement by TRAIL attenuated cellular ATP levels by robustly stimulating P-gp ATPase activity, and thus triggered P-gp-dependent apoptosis by depletion of the cellular ATP pool. In addition to hyperactive P-gp-mediated ATP hydrolysis, TRAIL-induced, P-gp-potentiated apoptosis was associated with activation of caspases-6, -7, -8, and -9; Bid cleavage; and mitochondrial depolarization. P-gp interacted with the TRAIL receptors DR4, DR5, and DcR1 in plasma membranes and enhanced TRAIL binding to DR5. Interestingly, the decreased level of the decoy TRAIL receptor, DcR1, in BC-19 cells further sensitized these cells to TRAIL. Therefore, both extrinsic and intrinsic apoptosis pathways are involved in this process. These findings for the first time reveal that TRAIL treatment preferentially causes apoptosis in P-gp-overexpressing MDR cells, and suggests significant clinical implications for the use of TRAIL in treating neoplasms that have failed chemotherapy.

Keywords: Abbreviations; DOX; doxorubicin; FADD; Fas associated death domain; MDR; multidrug resistance; P-gp; P-glycoprotein; ROS; reactive oxygen species; TNF-α; tumor necrosis factor-α; TNFR1; tumor necrosis factor-α receptor 1; TRAIL; tumor necrosis factor-related apoptosis-inducing ligandTRAIL; Apoptosis; Caspases; MDR; 1 gene; P-glycoprotein

In vitro and in vivo studies of a novel potential anticancer agent of isochaihulactone on human lung cancer A549 cells by Yi-Lin Chen; Shinn-Zong Lin; Jang-Yang Chang; Yeung-Leung Cheng; Nu-Man Tsai; Shee-Ping Chen; Wen-Liang Chang; Horng-Jyh Harn (pp. 308-319).

We previously demonstrated that the crude acetone extract of Bupleurum scorzonerifolium (BS-AE) 60μg/ml has anti-proliferation activity and apoptotic effects on A549 non-small cell lung cancer (NSCLC). A novel lignan, isochaihulactone (4-benzo[1,3]dioxol-5-ylmethyl-3(3,4,5-trimethoxyl-benzylidene)-dihydro-furan-2-one), was isolated from BS-AE and identified from spectral evidence (¹H NMR,¹³C NMR, IR, and MS) and by comparison with authentic synthetic standards. Isochaihulactone was cytotoxic (IC₅₀=10–50μM) in a variety of human tumor cell lines. In in vitro and in vivo microtubule assembly assays, it inhibited tubulin polymerization in a concentration-dependent manner. As determined by flow cytometry, isochaihulactone caused G2/M phase arrest and apoptosis in a time- and concentration-dependent manner. G2/M arrest was correlated with increased p21/WAF1 levels, downregulation of the checkpoint proteins cyclin B1/cdc2 and mobility shift of cdc25C. Moreover, isochaihulactone (30 and 50mg/kg) inhibited the growth of non-small cell lung carcinoma A549 xenograft in nude mice. These findings indicate isochaihulactone is a promising new antimitotic anticancer compound with potential for clinical application in the future.

Keywords: Bupleurum scorzonerifolium; Isochaihulactone; Microtubule destabilizing; Apoptosis; Cell cycle arrest

Novel amidine analogue of melphalan as a specific multifunctional inhibitor of growth and metabolism of human breast cancer cells by Krzysztof Bielawski; Anna Bielawska; Katarzyna Sosnowska; Wojciech Miltyk; Katarzyna Winnicka; Jerzy Pałka (pp. 320-331).

A novel amidine analogue of melphalan (AB4) was compared to its parent drug, melphalan in respect to cytotoxicity, DNA and collagen biosynthesis in MDA-MB-231 and MCF-7 human breast cancer cells. It was found that AB4 was more active inhibitor of DNA and collagen synthesis as well more cytotoxic agent than melphalan. The topoisomerase I/II inhibition assay indicated that AB4 is a potent catalytic inhibitor of topoisomerase II. Data from the ethidium displacement assay showed that AB4 intercalated into the minor-groove at AT sequences of DNA. The greater potency of AB4 to suppress collagen synthesis was found to be accompanied by a stronger inhibition of prolidase activity and expression compared to melphalan. The phenomenon was related to the inhibition of β₁-integrin and IGF-I receptor mediated signaling caused by AB4. The expression of β₁-integrin receptor, as well as Sos-1 and phosphorylated MAPK, ERK₁ and ERK₂ but not FAK, Shc, and Grb-2 was significantly decreased in cells incubated for 24h with 20μM AB4 compared to the control, not treated cells, whereas in the same conditions melphalan did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. These results indicate the amidine analogue of melphalan, AB4 represent multifunctional inhibitor of breast cancer cells growth and metabolism.

Keywords: Abbreviations; AB4; methyl 3-(4-(bis(2-chloroethyl)amino)phenyl)-2-(2-(4-[(; N; -isopropyl)amidino)]phenyl)furan-5-carboxamido)propanoate hydrochloride (amidine analogue of melphalan); DCI; N,; N; ′-carbonyldiimidazole; MTT; 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide; DMEM; Dulbecco's minimal essential medium; ERK; ₁; and ERK; ₂; extracellular-signal-regulated kinase 1 and kinase 2; FAK; non-receptor focal adhesion kinase pp125; ^FAK; FBS; fetal bovine serum; GRB2; growth-factor receptor-bound protein 2; IGF-I; insulin-like growth factor I; MAPK; mitogen activated protein kinases; PAGE; polyacrylamide gel electrophoresis; SDS; sodium dodecylsulfate; Sos-1; son of sevenless protein 1Melphalan; Topoisomerases; Breast cancer cells; Collagen biosynthesis; IGF-I receptor; β; ₁; -Integrin

Gene expression profiling changes induced by a novel Gemini Vitamin D derivative during the progression of breast cancer by Hong Jin Lee; Hao Liu; Catherine Goodman; Yan Ji; Hubert Maehr; Milan Uskokovic; Daniel Notterman; Michael Reiss; Nanjoo Suh (pp. 332-343).

We investigated gene expression changes induced by a novel Gemini Vitamin D₃ analog, RO-438-3582 (1α,25-dihydroxy-20 S-21(3-hydroxy-3-methyl-butyl)-23-yne-26,27-hexafluoro-cholecalciferol, Ro3582), in a unique human breast MCF10 model. We used two breast epithelial cell lines from this model, namely MCF10AT1 ( Ha-ras oncogene transfected MCF10A, early premalignant) and MCF10CA1a (fully malignant and metastatic derived from the MCF10AT1 line). We analyzed gene expression changes induced by Ro3582 using GeneChip technology, quantitative RT-PCR, Western blot analysis, or a gene transcription assay. Interestingly, we found distinct gene expression profile differences between Ro3582-induced response of the early premalignant MCF10AT1 and the malignant and metastatic MCF10CA1a cell lines. Moreover, while the Gemini Vitamin D₃ analog Ro3582 modulated the expression of several Vitamin D target genes such as the 24-hydroxylase, CD14, osteocalcin, and osteopontin in both cell lines, Ro3582 regulated many genes involved in cell proliferation and apoptosis, cell adhesion, invasion, angiogenesis as well as cell signaling pathways, such as the BMP and TGF-β systems, differently in the two cell lines. The Gemini Vitamin D₃ analog Ro3582 induced more significant gene changes in the early premalignant MCF10AT1 cells than in the malignant metastatic MCF10CA1a cells, suggesting that Gemini Vitamin D₃ analogs may be more effective in preventing the progression of an early stage of breast carcinogenesis than in treating late stage breast cancer.

Keywords: Abbreviations; BMP; bone morphogenetic protein; CTGF; connective tissue growth factor; IGFBP-3; insulin-like growth factor binding protein-3; JNK; C-jun N-terminal kinase; MMPs; matrix metalloproteinases; TGF-β; transforming growth factor-β; TIMPs; tissue inhibitors of matrix metalloproteinases; VDR; Vitamin D receptorMCF10; Breast cancer; Gemini Vitamin D; ₃; Bone morphogenetic protein; TGF-β; Smad3

Kinetic analysis of the protection afforded by reversible inhibitors against irreversible inhibition of acetylcholinesterase by highly toxic organophosphorus compounds by Saskia Eckert; Peter Eyer; Harald Mückter; Franz Worek (pp. 344-357).

In organophosphate poisoning, the underlying mechanism of the therapeutic efficacy of carbamate prophylaxis, which was successfully tested in animal experiments, still awaits complete understanding. In particular, it is unclear whether survival is improved by increased acetylcholinesterase activity during the acute phase, when both carbamate and organophosphate are present. This question should be solved experimentally by means of a dynamically working in vitro model. Immobilized human erythrocytes were continuously perfused while acetylcholinesterase activity was monitored in real-time by a modified Ellman method. The concentrations of reversible inhibitors and of paraoxon were varied to assess the influence of both components on the enzyme activity under steady-state conditions. Physostigmine, pyridostigmine and huperzine A were tested for their prophylactic potential. Upon pretreatment with these reversible inhibitors the enzyme was inhibited by 20–90%. Additional perfusion with 1μM paraoxon for 30min resulted in a residual activity of 1–4%, at low and high pre-inhibition, respectively. The residual activity was significantly higher than in the absence of reversibly blocking agents (0.3%). After discontinuing paraoxon, the activity increased even in the presence of the reversible blockers. Stopping the reversibly blocking agents resulted in 10–35% recovery of the enzyme activity, depending on the degree of pre-inhibition. The experimental results agreed with computer simulations upon feeding with the essential reaction rate constants, showing that physostigmine was somewhat superior to pyridostigmine in enhancing residual activity in the presence of 1μM paraoxon for 30min. The model predicts that inhibitors with a faster dissociation rate, e.g. huperzine A, may be superior in case of a ‘hit-and-run’ poison such as soman.

Keywords: Abbreviations; AChE; acetylcholinesterase (EC 3.1.1.7); AU; absorbance units; DTNB; 5,5′-dithiobis(2-nitrobenzoic acid); HI 6; 1-[[[4-(aminocarbonyl)-pyridinio]methoxy]methyl]-2-[(hydroxyimino)methyl]pyridinium dichloride; HLö 7; 1-[[[4-(aminocarbonyl)-pyridinio]methoxy]methyl]-2,4-bis[(hydroxyimino)methyl]pyridinium dimethanesulfonate; Hup A; (−)-huperzine A; Physo; (−)-physostigmine; Pyr; pyridostigmine; Px; paraoxon; RBC; red blood cell; TMB-4; (1,1′-trimethylene bis[4-(hydroxyimino)methyl]pyridinium dibromideCarbamate prophylaxis; Organophosphorus compounds; Acetylcholinesterase; Pyridostigmine; Physostigmine; Huperzine A; Kinetic analysis; Computer simulation

Development of a dynamic model for real-time determination of membrane-bound acetylcholinesterase activity upon perfusion with inhibitors and reactivators by Saskia Eckert; Peter Eyer; Harald Mückter; Franz Worek (pp. 358-365).

Quantitative predictions of the course of acetylcholinesterase (AChE) activity, following interference of inhibitors and reactivators, are usually obscured by the time-dependent changes of all reaction partners. To mimic these dynamics we developed an in vitro model. Immobilized human erythrocyte ghosts in a bioreactor were continuously perfused while AChE activity was monitored by a modified Ellman method. The perfusion system consisted of two HPLC pumps with integrated quaternary low-pressure gradient formers that were programmed by a computer using commercial HPLC software. The combined eluates passed a particle filter (Millex^®-GS, 0.22μm) containing a thin layer of erythrocytes that was immersed in a temperature-controlled water bath. The effluent passed a flow cell in a UV–vis detector, the signal of which was digitized, written to disc and calculated with curve fitting programs. AChE activity decreased by 3.4% within 2.5h. The day-to-day variation of the freshly prepared bioreactor using the same enzyme source was ±3.3%. Residual activity of 0.2% marked the limit of quantification. Following perfusion with paraoxon, pseudo first-order rate constants of inhibition were established that did not differ from results obtained in conventional assays. The same holds true for reactivation with obidoxime. The set-up presented allows freely programmable time-dependent changes of up to eight solvents to mimic pharmacokinetic profiles without accumulation of products. Due to some hysteresis in the system, reaction half-lives should be >3min and concentration changes in critical compounds should exceed half-lives of 5min. Otherwise, the system offers much flexibility and operates with high precision.

Keywords: Abbreviations; AChE; acetylcholinesterase (EC 3.1.1.7); AU; absorbance units; DTNB; 5,5′-dithiobis(2-nitrobenzoic acid); HPLC; high performance liquid chromatographyAcetylcholinesterase; Bioreactor; Perfusion; Paraoxon; Obidoxime; Real-time determination

NRH:quinone oxidoreductase 2 (NQO2) catalyzes metabolic activation of quinones and anti-tumor drugs by Claudia M. Celli; Namphuong Tran; Richard Knox; Anil K. Jaiswal (pp. 366-376).

NRH:quinone oxidoreductase 2 (NQO2) is a cytosolic flavoprotein that utilizes NRH as electron donor. The present studies investigate the role of NQO2 in metabolic detoxification/activation of quinones and quinone based anti-tumor drugs. Chinese hamster ovary (CHO) cells stably overexpressing cDNA derived mouse NQO2 and mouse keratinocytes from DMBA-induced skin tumors in wild-type and NQO2-null mice were generated. The CHO cells overexpressing NQO2 and mouse keratinocytes expressing or deficient in NQO2 were treated with varying concentrations of mitomycin C (MMC), CB1954, MMC analog BMY25067, EO9, menadione and BP-3,6-quinone, in the absence and presence of NRH. The cytotoxicity of the drugs was evaluated by colony formation. The CHO cells overexpressing higher levels of mouse NQO2 showed significantly increased cytotoxicity to menadione, BP-3,6-quinone and to the anti-tumor drugs MMC and CB1954 when compared to CHO cells expressing endogenous NQO2. The cytotoxicity increased in presence of NRH. Similar results were also observed with BMY25067 and EO9 treatments, but to a lesser extent. The results on keratinocytes deficient in NQO2 supported the data from CHO cells. The inclusion of NRH had no effect on cytotoxicity of quinones and drugs in keratinocytes deficient in NQO2. Mouse NQO2 protein was expressed in bacteria, purified and used to study the role of NQO2 in MMC-induced DNA cross-linking. Bacterially expressed and purified NQO2 efficiently catalyzed MMC activation that led to DNA cross-linking. These results concluded that NQO2 plays a significant role in the metabolic activation of both quinones and anti-tumor drugs leading to cytotoxicity and cell death.

Keywords: Abbreviations; BMY25067; analogue of mitomycin C; BP-3,6-quinone; benzo(a)pyrene-3,6-quinone; CB1954; 5-(aziridin-1-yl)-2,4-dinitrobenzamide also known as tretazicar; CHO; Chinese hamster ovary cells; EO9; indoloquinone; Menadione; 2-methyl-1,4-naphthoquinone; MMC; mitomycin C; mNQO2-rec; histidine tagged mouse NQO2 protein; NQO1; NAD(P)H:quinone oxidoreductase 1; NQO2; dihydronicotinamide riboside:quinone oxidoreductase 2; NRH; dihydronicotinamide riboside [nicotinamide riboside (reduced)]; 2,6-DCPIP; 2,6-dichlorophenolindophenolNRH:quinone oxidoreductase 2; Quinones; Anti-tumor drugs; Mitomycin C; Metabolic activation; Cytotoxicity

BE-I-PLA2, a novel acidic phospholipase A₂ from Bothrops erythromelas venom: Isolation, cloning and characterization as potent anti-platelet and inductor of prostaglandin I₂ release by endothelial cells by Jeanne Claine de Albuquerque Modesto; Patrick J. Spencer; Márcio Fritzen; Renata C. Valença; Maria Luíza Vilela Oliva; Marcia Bezerra da Silva; Ana Marisa Chudzinski-Tavassi; Miriam Camargo Guarnieri (pp. 377-384).

A novel acidic Asp49 phospholipase A₂ was isolated from Bothrops erythromelas (jararaca malha-de-cascavel) snake venom by four chromatographic steps. BE-I-PLA2 present a molecular weight of 13,649.57Da as estimated by mass spectrometry. N-terminal and four internal peptides were sequenced, covering around one-third of the complete toxin sequence. The complete BE-I-PLA2 cDNA was cloned from a B. erythromelas venom-gland cDNA library. The cDNA sequence possesses 457bp and encodes a protein with significant sequence similarity to many other phospholipase A₂ from snake venoms. When tested in platelet rich plasma, the enzyme showed a potent inhibitory effect on aggregation induced by arachidonic acid and collagen, but not ADP. On the other hand, BE-I-PLA2 did not modify aggregation in washed platelet. Furthermore, no action of BE-I-PLA2 on the principal platelets receptors was observed. Chemical modification with p-bromophenacyl bromide abolished the enzymatic activity of BE-I-PLA2, but its anti-platelet activity was only partially inhibited. In human umbilical-cord veins endothelial cells, BE-I-PLA2 was neither apoptotic nor proliferative but stimulated endothelial cells to release prostaglandin I₂, suggesting an increase of its potential anti-platelet activity in vivo. Further studies are required in order to determine the exact mechanism of action of BE-I-PLA2 in the inhibition of platelet aggregation.

Keywords: Phospholipase A; ₂; Snake venoms; Platelet; Platelet receptors; Endothelial cells; Prostaglandin I; ₂; Nitric oxide

Selective induction of intestinal CYP3A23 by 1α,25-dihydroxyvitamin D₃ in rats by Yang Xu; Kazunori Iwanaga; Changcheng Zhou; Matthew J. Cheesman; Federico Farin; Kenneth E. Thummel (pp. 385-392).

Enhancement of CYP3A transcription in both the small intestine and liver of the mouse by activation of a VDR signaling pathway was shown recently by Makishima et al. (Science, 2002). However, in humans and rats, hepatic VDR content is much lower than that found in small intestine, suggesting the possibility of tissue-selective responses to 1,25(OH)₂D₃. The purpose of this study was to determine the effect of 1,25(OH)₂D₃ on intestinal and hepatic CYP3A expression in the rat. We found that an acute intraperitoneal treatment (every 48h) in adult male rats with 1,25(OH)₂D₃ induced CYP3A transcription selectively in small intestine, but not in liver. At a dose of 100ng, there was a 6.6-fold increase in intestinal CYP3A23 mRNA after the third treatment ( p<0.05). There were concordant effects of 1,25(OH)₂D₃ treatment on intestinal CYP3A23 protein levels; 2.2-fold ( p<0.05), 3.5-fold ( p<0.05) and 4.8-fold ( p<0.01) increase following 1–3 doses of 100ng 1,25(OH)₂D₃, respectively. In contrast, there was no significant change of CYP3A23 protein content in liver at the 1,25(OH)₂D₃ doses tested. In support of these findings, there was a 366-fold and 77-fold higher level of VDR mRNA expression in the respective rat and human jejunal mucosa, compared to the liver. These data suggest that the human liver will be less sensitive than the intestine to the transcriptional effects of 1,25(OH)₂D₃ and that this regulatory pathway may contribute to inter-individual variability in constitutive intestinal CYP3A4 expression.

Keywords: Abbreviations; CYP; cytochrome P450; VDR; vitamin D receptor; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; 1,25(OH); ₂; D; ₃; 1α,25-dihydroxyvitamin D; ₃; 1α-(OH)D; ₃; 1α-hydroxyvitamin D; ₃; i.p.; intraperitoneal; PCR; polymerase chain reaction; NS; not significantCytochrome P450; CYP3A23; 1α,25-Dihydroxyvitamin D; ₃; VDR; Small intestine; Induction

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Biochemical Pharmacology (v.72, #3)