Induction of Cyp1a1 Is a Nonspecific Biomarker of Aryl Hydrocarbon Receptor Activation: Results of Large Scale Screening of Pharmaceuticals and Toxicants in Vivo and in Vitro

Hu, Wanglai; Sorrentino, Claudio; Denison, Michael S.; Kolaja, Kyle L.; Fielden, Mark R.

doi:10.1124/mol.106.032748

Cited by 190 publications

(154 citation statements)

References 40 publications

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“…Several studies have demonstrated that LEF is a ligand of the Aryl Hydrocarbon Receptor (AhR) [21][22][23] , which regulates the expression of CYP1A1/2. Consistently, we determined that LEF significantly induced CYP1A1/2 expression in both primary rat and human hepatocytes (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

Wang

et al. 2016

Acta Pharmacol Sin

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Aim: Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo. Methods: The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro. Hepatic cytochrome P450 reductase null (HRN) mice were used to examine the PK profiling and hepatotoxicity of leflunomide in vivo. The expression and function of sodium/bile acid cotransporter (NTCP) were assessed in rat and human hepatocytes and NTCP-transfected HEK293 cells. After Male Sprague-Dawley (SD) rats were administered teriflunomide (1,6, 12 mg • kg, ig) for 4 weeks, their blood samples were analyzed. Results: A nonspecific CYPs inhibitor aminobenzotriazole (ABT, 1 mmol/L) decreased the IC 50 value of leflunomide in rat hepatocytes from 409 to 216 μmol/L, whereas another nonspecific CYPs inhibitor proadifen (SKF, 30 μmol/L) increased the cellular accumulation of leflunomide to 3.68-fold at 4 h. After oral dosing (15 mg/kg), the plasma exposure (AUC 0-t ) of leflunomide increased to 3-fold in HRN mice compared with wild type mice. Administration of leflunomide (25 mg • kg -1 • d -1 ) for 7 d significantly increased serum ALT and AST levels in HRN mice; when the dose was increased to 50 mg • kg, all HRN mice died on d 6. Teriflunomide significantly decreased the expression of NTCP in human hepatocytes, as well as the function of NTCP in rat hepatocytes and NTCP-transfected HEK293 cells. Four-week administration of teriflunomide significantly increased serum total bilirubin and direct bilirubin levels in female rats, but not in male rats. Conclusion: Hepatic CYPs play a critical role in detoxification process of leflunomide, whereas the major metabolite teriflunomide suppresses the expression and function of NTCP, leading to potential cholestasis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

Wang

et al. 2016

Acta Pharmacol Sin

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“…Since the initial discovery that the AhR binds toxic polychlorinated and polynuclear aromatic hydrocarbons, it has subsequently been shown that the AhR also binds structurally and functionally diverse ligands, including health-promoting phytochemicals such indole-3-carbinol, flavonoids and extracts from fruits and vegetables, and a growing list of pharmaceuticals including omeprazole and other benzimidazoles (Bjeldanes et al, 1991;Denison et al, 1998;Song et al, 2002;Jeuken et al, 2003;Henry et al, 2006;Hu et al, 2007;Safe et al, 2012). In addition, structurally diverse "endogenous" biochemicals have been identified as AhR ligands, and there is evidence that the tryptophan photoproduct 6-formylindolo [3,2-b] carbazole (FICZ) and kynurenine may function as an endogenous ligand for the AhR (Song et al, 2002;Oberg et al, 2005;Henry et al, 2006;Wincent et al, 2009;Opitz et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes

et al. 2015

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The tryptophan microbiota metabolites indole-3-acetate, indole-3-aldehyde, indole, and tryptamine are aryl hydrocarbon receptor (AhR) ligands, and in this study we investigated their AhR agonist and antagonist activities in nontransformed young adult mouse colonocyte (YAMC) cells. Using Cyp1a1 mRNA as an Ah-responsive end point, we observed that the tryptophan metabolites were weak AhR agonists and partial antagonists in YAMC cells, and the pattern of activity was different from that previously observed in CaCo2 colon cancer cells. However, expansion of the end points to other Ah-responsive genes including the Cyp1b1, the AhR repressor (Ahrr), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TiParp) revealed a highly complex pattern of AhR agonist/antagonist activities that were both ligand-and genedependent. For example, the magnitude of induction of Cyp1b1 mRNA was similar for TCDD, tryptamine, and indole-3-acetate, whereas lower induction was observed for indole and indole-3-aldehyde was inactive. These results suggest that the tryptophan metabolites identified in microbiota are selective AhR modulators.

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“…It is also reported that some statins significantly induced cyp1a1 in kidney but rather weakly in the liver, suggesting that statins act as AhR ligands mainly in the kidney. 32 Conversely, the renal activation of slco4c1 by flutamide and omeprazole was quite weak (Supplemental Figure 3C). Thus, further exploring for drugs that upregulate human SLCO4C1 only in the kidney much more potently than statins should be a new clinical tool for patients with CKD and ADPKD to decelerate renal damage and to delay initiating hemodialysis.…”

mentioning

confidence: 99%

“…31 Because of the prominently catalyzing role, it has been believed that compounds that induce cyp1a1 activation are detrimental to humans and animals; however, it is also reported that induction of cyp1a1 is a sensitive but nonspecific indicator of AhR binding and activity, and the induction of cyp1a1 and activation of AhR are not synonymous with dioxinlike toxicity, including carcinogenesis. 32 Clinically, various weak AhR ligands, such as flutamide, omeprazole, and atorvastatin, were identified 32 but the Food and Drug Administration approves usage of these compounds, and in fact, they do not produce dioxin-like toxicities, including carcinogenesis in humans. Because statins have been used for a long time with a high safety and tolerability profile, induction of SLCO4C1 by statins in the kidney in patients with CKD and ADPKD may be a safe and new therapeutic tool to excrete uremic toxins and for reduction of renal inflammation.…”

mentioning

confidence: 99%

SLCO4C1 Transporter Eliminates Uremic Toxins and Attenuates Hypertension and Renal Inflammation

Toyohara¹,

Suzuki²,

Morimoto³

et al. 2009

Journal of the American Society of Nephrology

124

133

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Hypertension in patients with chronic kidney disease (CKD) strongly associates with cardiovascular events. Among patients with CKD, reducing the accumulation of uremic toxins may protect against the development of hypertension and progression of renal damage, but there are no established therapies to accomplish this. Here, overexpression of human kidney-specific organic anion transporter SLCO4C1 in rat kidney reduced hypertension, cardiomegaly, and inflammation in the setting of renal failure. In addition, SLCO4C1 overexpression decreased plasma levels of the uremic toxins guanidino succinate, asymmetric dimethylarginine, and the newly identified trans-aconitate. We found that xenobiotic responsive element core motifs regulate SLCO4C1 transcription, and various statins, which act as inducers of nuclear aryl hydrocarbon receptors, upregulate SLCO4C1 transcription. Pravastatin, which is cardioprotective, increased the clearance of asymmetric dimethylarginine and trans-aconitate in renal failure. These data suggest that drugs that upregulate SLCO4C1 may have therapeutic potential for patients with CKD.

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Induction of Cyp1a1 Is a Nonspecific Biomarker of Aryl Hydrocarbon Receptor Activation: Results of Large Scale Screening of Pharmaceuticals and Toxicants in Vivo and in Vitro

Cited by 190 publications

References 40 publications

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

Inhibition of hepatic cytochrome P450 enzymes and sodium/bile acid cotransporter exacerbates leflunomide-induced hepatotoxicity

Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes

SLCO4C1 Transporter Eliminates Uremic Toxins and Attenuates Hypertension and Renal Inflammation

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