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Increased acetaminophen hepatotoxicity in the NaS1 sulphate transporter null mouse

S. Lee, P.A. Dawson and D. Markovich, School of Biomedical Sciences, University of Queensland, Brisbane, QLD 4072, Australia.

Sulphate (SO42-) plays an important role in the detoxification of numerous xenobiotics, including the widely used analgesic drug, acetaminophen (APAP) (Cole & Evrovski, 2000). The Na+-SO42- cotransporter, NaS1 is expressed in the kidney, where it maintains blood sulphate levels (Markovich, 2001). NaS1 knock-out (Nas1-/-) mice exhibit hyposulphataemia and hypersulphaturia (Dawson et al. 2003). This project assessed the molecular, biochemical and physiological consequences of APAP challenge. Male Nas1+/+ and Nas1-/- mice aged 1-4 months (n= 5-7 mice), were injected with 125-, 250- or 500-mg/kg of APAP i.p. The animals were sacrificed at various times (0, 2, 4, 5, 6 and 12 hours) after APAP administration. Serum alanine aminotransferase (ALT) levels in Nas1+/+ and Nas1-/- mice were measured as an indicator of APAP-induced liver injury. ALT levels were 3-fold higher in Nas1-/- mice when compared to Nas1+/+ mice at 12 hours after APAP treatment (250-mg/kg). This supports our histological findings of increased cellular damage in Nas1-/- mice. Extensive haemorrhaging was observed in lobular areas of Nas1-/- mice (500-mg/kg APAP, t=5 hours post-injection) but not in Nas1+/+ mice. Hepatic glutathione (GSH) depletion was greater in Nas1-/- mice (87% reduction), compared to Nas1+/+ mice (63% reduction) at 250-mg/kg dosage regime (t=2 hours post-injection) whereas repletion of GSH showed no significant differences between and Nas1+/+ and Nas1-/-mice. The GSTpi mRNA levels were significantly induced (2-fold) in Nas1-/- mice, when compared to Nas1+/+ mice. The induction of GSTpi mRNA levels in APAP-treated Nas1-/- mice, could be a compensatory response to the GSH depletion. The mRNA levels of CYP3A11, which are responsible for the production of reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI) (Zhang et al., 2002), were significantly increased (1.5-fold) in Nas1-/- mice when compared to Nas1+/+ mice (250-mg/kg APAP, t=2 hours post-injection). In summary, we have identified increased APAP-induced hepatotoxicity and more rapid GSH depletion in the hyposulphataemic Nas1-/- mice and this may be due to low blood sulphate levels, which limits APAP sulphonation. This study suggests the potential role of NaS1 in the modulation of APAP-induced hepatotoxicity.

Cole, D.E. & Evrovski, J. (2000) Critical Reviews in Clinical Laboratory Sciences 37, 299-344.

Dawson, P.A., Beck, L. & Markovich, D. (2003) Proceedings of the National Academy of Science U.S.A. 100, 13704-13709.

Markovich, D (2001) Physiological Reviews 81, 1499-1534.

Zhang, J., Huang, W., Chua, S.S., Wei, P. & Moore, D.D. (2002) Science 298, 422-424.