Effect of malaria on phenol conjugation pathways in perfused rat liver.
The effect of malaria infection (MI) on sulphation and glucuronidation of phenol was investigated in single-pass perfused livers from rats infected with the rodent malaria parasite Plasmodium berghei. At a hepatic inflow (Cin) phenol concentration of 1 microgram/mL in controls, 52% was metabolized to sulphate conjugate and 37% to glucuronide conjugate at steady state. At this Cin, MI had no effect on phenol clearance (CL) (control: 9.63 +/- 0.38 vs MI: 9.65 +/- 0.36 mL/min; P greater than 0.05) or on the formation clearance (CLm) of the glucuronide or sulphate conjugates of phenol. When phenol Cin was increased 10-fold to 10 micrograms/mL, 6% was metabolized to sulphate conjugate and 94% to glucuronide conjugate. At this Cin phenol CL was decreased significantly (control: 9.44 +/- 0.46 vs MI: 7.09 +/- 1.51 mL/min; P less than 0.05) and represented a decrease in intrinsic clearance (sinusoidal perfusion model) of at least 55%. This decrease was accounted for entirely by the decrease in the CLm of the glucuronide conjugate (control: 8.88 +/- 0.96 vs 5.98 +/- 1.87 mL/min; P less than 0.05), whereas the CLm of the sulphate conjugate was unchanged. There was a negative correlation between phenol glucuronide CLm and the severity of the erythrocytic parasitaemia (r2 = 0.75, P less than 0.05). The dose-dependent reduction in phenol glucuronidation in MI may be due to reduced availability of the cosubstrate uridine diphosphoglucuronic acid (UDPGA), because previous studies have shown that UDPGA availability depends on glycogen stores, which are known to be reduced in MI. These data suggest that sulphate conjugation is preserved in MI and that glucuronidation is preserved at low doses of substrate. At high substrate doses, glucuronidation is impaired in MI and the impairment correlates with the severity of the infection.
Murdoch
R T
RT
Department of Medicine, University of Melbourne, Repatriation Hospital, Australia.
Ghabrial
H
H
Smallwood
R A
RA
Morgan
D J
DJ
D000818:Animals; D004912:Erythrocytes / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008288:Malaria / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D019800:Phenol; D010636:Phenols / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism
D005965:Glucuronates; D010636:Phenols; D013431:Sulfates; D019800:Phenol