Effects of inhibition of hepatic sulfotransferase activity on renal genotoxicity induced by lucidin‐3‐O‐primeveroside. Issue 4 (12th December 2018)

• Record Type: Journal Article
• Authors: Ishii, Yuji; Kijima, Aki; Takasu, Shinji; Ogawa, Kumiko; Umemura, Takashi
• Is Part Of: Journal of applied toxicology. Volume 39:Issue 4(2019)
• Page Start: 650
• Page End: 657
• Publication Date: 2018-12-12
• Subjects: DNA adduct -- gene mutation -- lucidin‐3‐O‐primeveroside -- sulfotransferase; Toxicology -- Periodicals; Industrial toxicology -- Periodicals; Environmentally induced diseases -- Periodicals; Toxicology -- Periodicals; 615.9005
• DOI: 10.1002/jat.3755
• Languages: English
• ISSNs: 0260-437X

Abstract

Abstract: Sulfotransferase 1A (SULT1A) expression is lower in the liver of humans than that of rodents. Therefore, species differences should be taken into consideration when assessing the risk of rodent hepatocarcinogens metabolically activated by SULT1A in humans. Although some renal carcinogens require SULT1A‐mediated activation, it is unclear how SULT1A activity in the liver affects renal carcinogens. To explore the effects of SULT1A activity in the liver on genotoxicity induced by SULT1A‐activated renal carcinogens, B6C3F1 mice or gpt delta mice of the same strain background were given lucidin‐3‐ O ‐primeveroside (LuP), a hepatic and renal carcinogen of rodents, for 4 or 13 weeks, respectively, and pentachlorophenol (PCP) as a liver‐specific SULT inhibitor, was given from 1 week before LuP treatment to the end of the experiment. A 4 week exposure of LuP induced lucidin‐specific DNA adduct formation. The suppression of Sult1a expression was observed only in the liver but not in the kidneys of PCP‐treated mice, but co‐administration of PCP suppressed LuP‐induced DNA adduct formation in both organs. Thirteen‐week exposure of LuP increased mutation frequencies and cotreatment with PCP suppressed these increases in both organs. Given that intact levels of SULT activity in the liver were much higher than in the kidneys of rodents, SULT1A may predominantly activate LuP in the liver, consequently leading to genotoxicity not only in the liver but also in the kidney. Thus, species differences should be considered in human risk assessment of renal carcinogens activated by SULT1A as in the case of the corresponding liver carcinogens. Abstract : Species differences in expression levels of hepatic sulfotransferase 1A (SULT1A) result in major concerns regarding the extrapolation of rodent data of SULT1A‐activated hepatic genotoxicity and/or carcinogenicity to humans. The present study showed that hepatic SULT1A played a crucial role in lucidin‐3‐ O ‐primeveroside‐induced DNA adduct formation and in vivo mutagenicity in the kidneys of mice. Our data imply that species differences should be considered when rodent data on renal genotoxicity and carcinogenicity of SULT1A‐activated chemicals are extrapolated to humans.