Enhanced nephrotoxicity of acetaminophen in fructose-induced hypertriglyceridemic rats: Contribution of oxidation and deacetylation of acetaminophen to an enhancement of nephrotoxicity

Diabetes and hypertriglyceridemia modify the mode of acetaminophen-induced hepatotoxicity and nephrotoxicity in rats and mice

“…Diabetes is also considered to alter the mode of APAP-induced nephrotoxicity judging from the reports of the effects of diabetes on other chemicals-induced nephrotoxicity, although there are no reports directly dealing with the effects of diabetes on APAP-induced nephrotoxicity. In addition, there are very interesting reports that in fructose-induced hypertriglyceridemic rats, as compared with normal ones, hepatotoxicity of APAP is apparently less severe, whereThe mechanisms of alteration of APAP-induced hepatorenal toxicity under hypertriglyceridemic condition are well discussed by Ishida et al (1997aIshida et al ( , 1997bIshida et al ( and 1997d Differing from diabetic animals, fructose-induced hypertriglyceridemic rats show only an increase in plasma triglyceride level, and so they are considered to be of great -demia, which is a representative lifestyle-related disease in a modern society, on the mode of toxicity of various chemicals.…”

“…In contrast, in SD rats, which are more resistant to APAP nephrotoxicity than F344 rats, this deacetylation pathway APAP (Mugford and Tarloff, 1995). Ishida et al (1997a) reported that the inhibition of APAP oxidation by piperonyl butoxide, a cytochrome P-450 inhibitor, or inhibition of deacetylation by bis(p-nitrophenyl)phosphate, carboxyesterase inhibitor, did not alter APAP-induced renal lesions in the non-pretreated SD rats while these inhibitors protected fructose-pretreated SD rats from APAP nephrotoxicity. These results indicate that the enhancement of APAP-induced nephrotoxicity in fructose-pretreated SD rats is due not only to cytochrome P-450-Vol.…”

“…In the study conducted by Hojo et al (2000), rats received a single oral administration of extremely high doses of sucrose (1.8 to 3.4 g/kg) concomitant with oral APAP. In contrast, rats received a single ip injection of APAP after 3 or 5 weeks of pretreatment with fructose in drinking water ad libitum in the studies reported by Ishida et al (1995Ishida et al ( , 1997a. Ishida et al (1997d) also reported that renal APAPconcentrations during the early phase (15 and 30 min fructose-pretreated rats than those in normal ones and plasma and hepatic APAP concentrations in fructose-pretreated rats were greater than those in normal ones only at the later phase (plasma: 6 hr; liver: 6 and 12 hr after APAP-administration).…”

“…1 mediated oxidation of APAP but also to its cytochrome P-450-independent deacetylation which is not responsible for APAP-induced nephrotoxicity in normal SD rats. In addition, since there were no differences in the severity of gentamicin- (Tarloff and Goldstein, 1994), chloroform- (Pohl et al, 1977;Kluwe and Hook, 1981), or 45 minischemia/reperfusion-induced renal lesions (Arnold et al, 1986;Shapiro et al, 1987Shapiro et al, , 1989Mourelle et al, 1991) between the non-pretreated and the fructose-pretreated rats (Ishida et al, 1997a), alterations in APAP-specific pharmacokinetics and metabolism may play an important role in enhancement of APAP nephrotoxicity in fructosepretreated rats.…”

“…From the above-mentioned experiments, Ishida et al (1997a) concluded that the enhancement of APAPinduced nephrotoxicity observed in the fructose-pretreated SD rats is attributable to at least the following two factors: 1) an increase in renal APAP concentration at the early phase (15 and 30 min after APAP dosing) and 2) enhanced bioactivation of APAP via two metabolic pathways: cytochrome P-450-mediated oxidation of APAP to NAPQI and cytochrome P-450-independent deacetylation of APAP to PAP which is not responsible for nephrotoxicity in normal SD rats (Figs. 2 and 3).…”