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High Content Screening Analysis to Evaluate the Toxicological Effects of Harmful and Potentially Harmful Constituents (HPHC)
Published on: May 10, 2016
Interactions of human organic anion transporter 1 (hOAT1) with substances associated with forensic toxicology
Shoetsu Chiba1, Toru Ikawa, Hiroshi Takeshita
1Department of Legal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japan. chiba@marianna-u.ac.jp
Abstract:
Renal excretion is an important elimination pathway for substances associated with forensic toxicology, such as medicines, agricultural chemicals, and industrial chemicals. This study aimed to elucidate the renal elimination pathway of substances using culture cells stably expressing the human organic anion transporter 1 (hOAT1) gene. Substances tested were diazepam, triazolam, haloperidol, amitriptyline, mianserin, bromovalerylurea, phenobarbital, acetaminophen, acetylsalicylic acid, lidocaine, aconitine, atropine, caffeine, nicotine, malathion, dichlorvos, fenitrothion, chlorpyrifosmethyl, paraquat, diquat, potassium cyanide, sodium arsenite, sodium azide, o-cresol, and probenecid (control, a representative inhibitor of hOAT1). Results demonstrated that diazepam, triazolam, amitriptyline, mianserin, malathion, fenitrothion, chlorpyrifosmethyl, and probenecid significantly inhibited representative substrates of hOAT1 and para-aminohippuric acid uptake by hOAT1. IC(50) values of the aforementioned substances were 133.3, 185.2, 354.1, 312.6, 114.2, 26.6, 191.5, and 7.9μM, respectively. Ki values were 83.5, 86.0, 573.9, 99.0, 134.0, 51.2, 324.6, and 9.1μM, respectively. In conclusion, the current results suggest that fenitrothion and chlorpyrifosmethyl are transported with pharmacokinetics indicative of hOAT1 involvement in the human kidney.
Insights
This study investigated how the human organic anion transporter 1 (hOAT1) affects the renal excretion of toxic substances. Fenitrothion and chlorpyrifosmethyl show pharmacokinetics suggesting hOAT1 involvement in kidney transport.
Area of Science:
- Toxicology
- Pharmacokinetics
- Renal Physiology
Background:
- Renal excretion is a key elimination route for various xenobiotics, including pharmaceuticals and pesticides.
- Understanding the specific transporters involved in renal drug and toxin elimination is crucial for forensic toxicology.
- The human organic anion transporter 1 (hOAT1) plays a significant role in the active secretion of organic anions in the kidney.
Purpose of the Study:
- To elucidate the renal elimination pathways of forensic toxicological substances using cells expressing human organic anion transporter 1 (hOAT1).
- To identify which tested substances interact with and are potentially transported by hOAT1.
- To determine the inhibitory potential (IC50 and Ki values) of various compounds on hOAT1 function.
Main Methods:
- Utilized cell cultures stably expressing the human organic anion transporter 1 (hOAT1) gene.
- Assessed the inhibition of hOAT1 substrate (para-aminohippuric acid) uptake by a panel of forensic chemicals.
- Calculated half-maximal inhibitory concentration (IC50) and inhibition constant (Ki) values for significant inhibitors.
Main Results:
- Diazepam, triazolam, amitriptyline, mianserin, malathion, fenitrothion, chlorpyrifosmethyl, and probenecid significantly inhibited hOAT1-mediated uptake.
- Specific IC50 values ranged from 26.6 μM (fenitrothion) to 354.1 μM (amitriptyline).
- Specific Ki values ranged from 9.1 μM (probenecid) to 573.9 μM (amitriptyline), with fenitrothion and chlorpyrifosmethyl showing notable inhibition.
Conclusions:
- Fenitrothion and chlorpyrifosmethyl exhibit pharmacokinetic properties suggesting their transport is mediated by hOAT1 in the human kidney.
- These findings highlight the potential involvement of hOAT1 in the renal elimination of specific organophosphate pesticides.
- Further research is warranted to fully characterize the role of hOAT1 in the renal handling of xenobiotics in forensic contexts.
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