Mechanism of Chloroform-induced Renal Toxicity: Non-involvement of Hepatic Cytochrome P450-dependent Metabolism

Overview

Journal Toxicol Appl Pharmacol

Specialties Pharmacology
Toxicology

Date 2007 Nov 23

PMID 18031782

Citations 15

Authors

Cheng Fang

Melissa Behr

Fang Xie

Shijun Lu

Meghan Doret

Hongxiu Luo

Weizhu Yang

Kenneth Aldous

Xinxin Ding

Jun Gu

Affiliations

Soon will be listed here.

Abstract

Chloroform causes hepatic and renal toxicity in a number of species. In vitro studies have indicated that chloroform can be metabolized by P450 enzymes in the kidney to nephrotoxic intermediate, although direct in vivo evidence for the role of renal P450 in the nephrotoxicity has not been reported. This study was to determine whether chloroform renal toxicity persists in a mouse model with a liver-specific deletion of the P450 reductase (Cpr) gene (liver-Cpr-null). Chloroform-induced renal toxicity and chloroform tissue levels were compared between the liver-Cpr-null and wild-type mice at 24 h following differing doses of chloroform. At a chloroform dose of 150 mg/kg, the levels of blood urea nitrogen (BUN) were five times higher in the exposed group than in the vehicle-treated one for the liver-Cpr-null mice, but they were only slightly higher in the exposed group than in the vehicle-treated group for the wild-type mice. Severe lesions were found in the kidney of the liver-Cpr-null mice, while only mild lesions were found in the wild-type mice. At a chloroform dose of 300 mg/kg, severe kidney lesions were observed in both strains, yet the BUN levels were still higher in the liver-Cpr-null than in the wild-type mice. Higher chloroform levels were found in the tissues of the liver-Cpr-null mice. These findings indicated that loss of hepatic P450-dependent chloroform metabolism does not protect against chloroform-induced renal toxicity, suggesting that renal P450 enzymes play an essential role in chloroform renal toxicity.

Citing Articles

Studies on the ethnopharmacology, antimicrobial activity, and toxicity of (Vahl.) Endl., in rats.

Githua K, Maitho T, Nguta J, Okumu M F1000Res. 2023; 11:286.

PMID: 37767078 PMC: 10521044. DOI: 10.12688/f1000research.109243.2.

Acute liver injury in a non-alcoholic fatty liver disease patient with chloroform exposure: a case report.

Suehiro Y, Uchida T, Tsuge M, Murakami E, Miki D, Kawaoka T Clin J Gastroenterol. 2023; 16(2):250-253.

PMID: 36715860 DOI: 10.1007/s12328-023-01760-7.

Assessing cytochrome P450 function using genetically engineered mouse models.

Hannon S, Ding X Adv Pharmacol. 2022; 95:253-284.

PMID: 35953157 PMC: 10544722. DOI: 10.1016/bs.apha.2022.05.008.

3-D Human Renal Tubular Organoids Generated from Urine-Derived Stem Cells for Nephrotoxicity Screening.

Guo H, Deng N, Dou L, Ding H, Criswell T, Atala A ACS Biomater Sci Eng. 2020; 6(12):6701-6709.

PMID: 33320634 PMC: 8118570. DOI: 10.1021/acsbiomaterials.0c01468.

Chronic, Recreational Chloroform-Induced Liver Injury.

Minor E, Newman M, Kupec J Case Reports Hepatol. 2018; 2018:1619546.

PMID: 30275992 PMC: 6151676. DOI: 10.1155/2018/1619546.

References

Lock E, Reed C . Xenobiotic metabolizing enzymes of the kidney. Toxicol Pathol. 1998; 26(1):18-25. DOI: 10.1177/019262339802600102. View

Gu J, Chen C, Wei Y, Fang C, Xie F, Kannan K . A mouse model with liver-specific deletion and global suppression of the NADPH-cytochrome P450 reductase gene: characterization and utility for in vivo studies of cyclophosphamide disposition. J Pharmacol Exp Ther. 2007; 321(1):9-17. DOI: 10.1124/jpet.106.118240. View

Pass G, Carrie D, Boylan M, Lorimore S, Wright E, Houston B . Role of hepatic cytochrome p450s in the pharmacokinetics and toxicity of cyclophosphamide: studies with the hepatic cytochrome p450 reductase null mouse. Cancer Res. 2005; 65(10):4211-7. DOI: 10.1158/0008-5472.CAN-04-4103. View

Omura T, Sato R . THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. I. EVIDENCE FOR ITS HEMOPROTEIN NATURE. J Biol Chem. 1964; 239:2370-8. View

Porter T, Coon M . Cytochrome P-450. Multiplicity of isoforms, substrates, and catalytic and regulatory mechanisms. J Biol Chem. 1991; 266(21):13469-72. View

Anand S, Philip B, Palkar P, Mumtaz M, Latendresse J, Mehendale H . Adaptive tolerance in mice upon subchronic exposure to chloroform: Increased exhalation and target tissue regeneration. Toxicol Appl Pharmacol. 2006; 213(3):267-81. DOI: 10.1016/j.taap.2006.02.007. View

Letteron P, Degott C, Labbe G, Larrey D, Descatoire V, Tinel M . Methoxsalen decreases the metabolic activation and prevents the hepatotoxicity and nephrotoxicity of chloroform in mice. Toxicol Appl Pharmacol. 1987; 91(2):266-73. DOI: 10.1016/0041-008x(87)90107-4. View

Henderson C, Pass G, Wolf C . The hepatic cytochrome P450 reductase null mouse as a tool to identify a successful candidate entity. Toxicol Lett. 2005; 162(1):111-7. DOI: 10.1016/j.toxlet.2005.10.016. View

Gu J, Cui H, Behr M, Zhang L, Zhang Q, Yang W . In vivo mechanisms of tissue-selective drug toxicity: effects of liver-specific knockout of the NADPH-cytochrome P450 reductase gene on acetaminophen toxicity in kidney, lung, and nasal mucosa. Mol Pharmacol. 2004; 67(3):623-30. DOI: 10.1124/mol.104.007898. View

10.

Constan A, Sprankle C, Peters J, Kedderis G, Everitt J, Wong B . Metabolism of chloroform by cytochrome P450 2E1 is required for induction of toxicity in the liver, kidney, and nose of male mice. Toxicol Appl Pharmacol. 1999; 160(2):120-6. DOI: 10.1006/taap.1999.8756. View

11.

Van Vleet T, Schnellmann R . Toxic nephropathy: environmental chemicals. Semin Nephrol. 2003; 23(5):500-8. DOI: 10.1016/s0270-9295(03)00094-9. View

12.

Lilly P, Ross T, Pegram R . Trihalomethane comparative toxicity: acute renal and hepatic toxicity of chloroform and bromodichloromethane following aqueous gavage. Fundam Appl Toxicol. 1997; 40(1):101-10. DOI: 10.1006/faat.1997.2372. View

13.

Cummings B, Zangar R, Novak R, Lash L . Cellular distribution of cytochromes P-450 in the rat kidney. Drug Metab Dispos. 1999; 27(4):542-8. View

14.

Ma J, Qu W, Scarborough P, Tomer K, Moomaw C, Maronpot R . Molecular cloning, enzymatic characterization, developmental expression, and cellular localization of a mouse cytochrome P450 highly expressed in kidney. J Biol Chem. 1999; 274(25):17777-88. DOI: 10.1074/jbc.274.25.17777. View

15.

Gu J, Weng Y, Zhang Q, Cui H, Behr M, Wu L . Liver-specific deletion of the NADPH-cytochrome P450 reductase gene: impact on plasma cholesterol homeostasis and the function and regulation of microsomal cytochrome P450 and heme oxygenase. J Biol Chem. 2003; 278(28):25895-901. DOI: 10.1074/jbc.M303125200. View

16.

Black S, Coon M . P-450 cytochromes: structure and function. Adv Enzymol Relat Areas Mol Biol. 1987; 60:35-87. DOI: 10.1002/9780470123065.ch2. View

17.

Stec D, Flasch A, Roman R, White J . Distribution of cytochrome P-450 4A and 4F isoforms along the nephron in mice. Am J Physiol Renal Physiol. 2002; 284(1):F95-102. DOI: 10.1152/ajprenal.00132.2002. View

18.

Smith J, Hook J . Mechanism of chloroform nephrotoxicity. III. Renal and hepatic microsomal metabolism of chloroform in mice. Toxicol Appl Pharmacol. 1984; 73(3):511-24. DOI: 10.1016/0041-008x(84)90103-0. View

19.

Weng Y, Fang C, Turesky R, Behr M, Kaminsky L, Ding X . Determination of the role of target tissue metabolism in lung carcinogenesis using conditional cytochrome P450 reductase-null mice. Cancer Res. 2007; 67(16):7825-32. DOI: 10.1158/0008-5472.CAN-07-1006. View

20.

Anders M, Dekant W, Vamvakas S . Glutathione-dependent toxicity. Xenobiotica. 1992; 22(9-10):1135-45. DOI: 10.3109/00498259209051867. View