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TOXICOLOGY
Clinical Pharmacokinetics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
Received March 25, 2004; accepted June 14, 2004.
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Abstract |
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), and responses to a variety of drugs show 24-h rhythmicity. For example, a significant 24-h rhythm occurs for the anticonvulsant effect of sodium valproate, the analgesic effect of morphine, and the antitumor effects of antitumor drugs (Ohdo et al., 1988, 1996, 2001; Koyanagi et al., 2003; Yoshida et al., 2003). Conceptually, such variations may depend on changes in the sensitivity of target organs to a particular agent, alterations in drug metabolism, and/or rhythmic fluctuations in the availability of endogenous substances. Feeding schedules can also greatly modify biological rhythms, although lighting schedule is undoubtedly an important determinant of these rhythms. For example, the repeated manipulation of feeding schedule has a marked influence on the rhythms of the action or pharmacokinetics of several drugs in mice (Song et al., 1993a,b; Ohdo et al., 1996).
Acetaminophen (APAP) is a widely used analgesic drug and is mainly biotransformed and eliminated as nontoxic conjugates with glucuronic acid and sulfate (Nelson, 1995). Only a small portion of the dose is bioactivated by cytochrome P450 to N-acetyl-p-benzoquinone imine (NAPQI), a reactive toxic intermediate (Dahlin et al., 1984). This reaction is caused by cytochromes P450 CYP2E1 and CYP1A2 in mice. In animal studies, CYP2E1 is shown to directly affect the extent of APAP toxicity (Gonzalez, 1998). For APAP overdose, glucuronidation and sulfation are saturated, and the formation of NAPQI increases (Hjelle and Klaassen, 1984). Taken together, these data suggest that CYP2E1 plays a role in APAP bioactivation and toxicity in vitro and in vivo. Covalent binding to specific targets that may be important to cell viability might mediate the initiation of multiple events that would normally progress to toxicity. Evidence suggests that the covalent binding of APAP to protein is a reaction between NAPQI and cysteinyl sulfhydryl groups on protein, which produces the corresponding 3-(cysteine-S-yl) APAP protein adduct (Hoffmann et al., 1985). NAPQI depletes GSH, covalently binds to tissue micromolecules, and has been identified as the key metabolite that causes APAP toxicity (Mitchell et al., 1981).
Hepatic glutathione concentrations also vary in a time-dependent manner and exhibit an inverse relationship to the 24-h rhythm of APAP mortality. Lighting schedules and the fasting condition can alter the 24-h rhythms of APAP mortality and hepatic GSH levels in mice (Schnell et al., 1983, 1984). However, the 24-h rhythm of CYP2E1 activity in the liver and covalent binding of NAPQI in hepatic cells has not been clarified. Specifically, it is not known whether time-restricted feeding can modify the 24-h rhythm.
In the present study, we investigated the influence of, and potential mechanisms underlying, the repeated manipulation of feeding schedule on the 24-h rhythm of mortality and hepatotoxicity induced by APAP in mice.
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Materials and Methods |
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Preparation of Dosing Solutions. APAP was purchased from Wako Pure Chemicals (Osaka, Japan) and was dissolved in saline to yield an appropriate concentration of 30 or 15 mg/ml. It was then used delivered as an i.p. dose at 600 or 300 mg/kg by means of a 26-gauge needle connected to a 1-ml syringe at a volume of 20 ml/kg drug. Other reagents purchased from Wako Pure Chemicals or Sigma-Aldrich (St. Louis, MO) were of analytical grade and used without further purification.
Influence of Feeding Schedule on Dosing Time-Dependent Mortality and Hepatotoxicity. To study the 24-h toxicity rhythm of APAP, ALF, and TRF groups of 10 mice, each were given APAP (600 mg/kg i.p.) at 9:00 AM, 1:00 PM, 5:00 PM, 9:00 PM, 1:00 AM, or 5:00 AM, and the number of deaths was recorded 7 days after drug injection. To evaluate hepatotoxicity, the ALF and TRF groups were given APAP (300 mg/kg i.p.) at 9:00 AM or 9:00 PM. Blood samples were drawn only once from the heart of individual mice 2, 6, 12, or 24 h after APAP injection. Thus, the mice were used only once. The plasma enzyme activity of alanine aminotransferase (ALT) was measured using a GPT-UV test kit (Wako Pure Chemicals). Livers were removed 24 h after APAP injection, fixed in 10% buffered formalin for hematoxylin and eosin staining, and examined by light microscopy.
Influence of Feeding Schedule on Dosing Time-Dependent APAP Metabolites of NAPQI Covalent Binding. ALF and TRF groups of 10 mice each were injected with APAP (300 mg/kg i.p.) at 9:00 AM or 9:00 PM, and livers were removed at 2 h after the drug injection. Deparaffinized liver sections were placed in 3% hydrogen peroxide for 1 h to quench endogenous peroxidase activity and rinsed three times at 10 min for each wash with phosphate-buffered saline (PBS). After blocking nonspecific binding sites with 1.5% anti-goat IgG antibody for 1 h, sections were incubated in rabbit polyclonal antibody against APAP (Biogenesis, Kingston, NH; 1:250) for 1 h. The sections were then rinsed three times with 0.3% Triton X-100 (PBS) and incubated in biotinylated goat antibody against rabbit immunoglobulin for 1 h. They were again rinsed three times with 0.3% Triton X-100 (PBS) and then incubated in avidin-biotin solution for 1 h. Diaminobenzidine was used as chromogen, and each step was performed at room temperature except where otherwise stated.
Influence of Feeding Schedule on Time-Dependent Differences in Hepatic CYP2E1 Activity. Livers were removed from 10 untreated ALF and TRF group mice each at 9:00 AM, 1:00 PM, 5:00 PM, 9:00 PM, 1:00 AM, or 5:00 AM. Microsomal fractions were then prepared according to a previously reported method (Omura and Sato, 1964). CYP2E1 activity was estimated by measuring p-nitrophenol (PNP)-hydroxylation, and the hydroxylation of PNP to 4-nitrocatechol was determined by a previously reported procedure (Allis and Robinson, 1994). A substrate concentration of 100 µM PNP was used in this assay, and CYP2E1 activity was expressed as nanomoles per 4-nitrocatechol per minute per milligram of protein.
Influence of Feeding Schedule on Time-Dependent Differences in Hepatic GSH Levels. To study the rhythm of hepatic GSH levels, livers were removed from 10 untreated ALF and TRF group mice each at 9:00 AM, 1:00 PM, 5:00 PM, 9:00 PM, 1:00 AM, or 5:00 AM. To study the time course of hepatic GSH levels, 10 ALF and TRF group mice each were injected with APAP (300 mg/kg i.p.) or saline at 9:00 AM or 9:00 PM, and livers were removed before the drug injection or at 0.5, 2, or 6 h after injection. Briefly, the livers were homogenized with 100 mM sodium phosphate (pH 7.5) (1:5, w/v) on ice. The homogenate was then mixed with 4% sulfosalicylic acid (1:1) followed by centrifugation at 12,000 rpm for 15 min at 4°C. The supernatant was mixed with 10 mM sodium phosphate (pH 7.5) containing 0.5 mM EDTA, 4 mM NADPH, and 12 U/ml glutathione reductase and then incubated at 30°C for 5 min. To this, 10 mM 5,5'-dithiobis-(2-nitrobenzoic acid) was added, and the change in absorbance at 412 nm was quantified. Total glutathione was measured, and reduced glutathione was used as the standard.
Statistical Analysis. A 0.05 level of probability was used as the criteria for statistical significance, and the 
2 test was used for survival studies. Survival curves were compared using the log-rank test, and ANOVA and Tukey-Kramer's test were applied for the other analysis.
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Results |
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Influence of Feeding Schedule on Dosing Time-Dependent Hepatotoxicity. For the ALF group, plasma ALT activity 12 h after APAP (300 mg/kg i.p.) injection at 9:00 PM was significantly higher than that after the drug injection at 9:00 AM (P < 0.01) (Fig. 3A). Plasma ALT activity after APAP injection at 9:00 PM markedly increased and reached a peak 12 h after injection, whereas plasma ALT activity after APAP injection at 9:00 AM was not significantly different from that after saline injection at 9:00 AM. For the TRF group, plasma ALT activity 12 h after APAP injection at 9:00 AM was significantly higher than that after injection at 9:00 PM (P < 0.01) (Fig. 3B). Plasma ALT activity after APAP injection at 9:00 AM markedly increased and reached a peak 12 h after injection, whereas plasma ALT activity after APAP injection at 9:00 PM was not significantly different from that after saline injection at 9:00 PM. Within the ALF group, severe centrilobular hepatocellular necrosis was observed after APAP injection at 9:00 PM and not 9:00 AM (Fig. 4, A and B). Specifically, mice after APAP injection at 9:00 PM showed more hepatic damage than those after injection at 9:00 AM. For the TRF group, severe centrilobular hepatocellular necrosis was observed after APAP injection at 9:00 AM and not 9:00 PM (Fig. 4, C and D). Mice after APAP injection at 9:00 AM showed more hepatic damage than those after injection at 9:00 PM.
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Influence of Feeding Schedule on Dosing Time-Dependent APAP Metabolite NAPQI Covalent Binding. For the ALF group, immunohistochemical staining using anti-APAP antibody 2 h after APAP (300 mg/kg i.p.) injection was observed in the centrilobular region of the liver after the drug injection at 9:00 PM but not after injection at 9:00 AM (Fig. 5, A and B). This suggests that a greater extent of APAP-protein adduct formation occurred in the livers of mice after injection at 9:00 PM. Within the TRF group, immunohistochemical staining 2 h after APAP injection was observed in the centrilobular region of the liver after APAP injection at 9:00 AM but not after the drug injection at 9:00 PM (Fig. 5, C and D). These results suggest that a greater extent of APAP-protein adduct formation occurred in the livers of mice after injection at 9:00 AM.
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Influence of Feeding Schedule on Time-Dependent Differences in Hepatic CYP2E1 Activity. For the ALF group, hepatic CYP2E1 activity in the untreated mice showed a significant 24-h rhythm with higher levels at 9:00 PM and 1:00 AM and lower levels at 9:00 AM and 1:00 PM (P < 0.01) (Fig. 6). Within the TRF group, hepatic CYP2E1 activity in the untreated mice showed a significant 24-h rhythm with higher levels at 5:00 AM and 9:00 AM and lower levels at 9:00 PM (P < 0.01). The TRF group had a markedly different rhythm of hepatic CYP2E1 activity than that of the ALF group.
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Influence of Feeding Schedule on Time-Dependent Differences in Hepatic GSH Levels. For the ALF group, hepatic GSH levels in the untreated mice showed a significant 24-h rhythm with higher levels at 9:00 AM and lower levels at 5:00 PM and 9:00 PM (P < 0.01) (Fig. 7). For the TRF group, hepatic GSH levels in the untreated mice showed a significant 24-h rhythm with higher levels at 5:00 PM and lower levels at 9:00 AM and 5:00 AM (P < 0.01). Within the ALF group, hepatic GSH levels after APAP (300 mg/kg i.p.) injection at 9:00 AM or 9:00 PM significantly decreased compared with those after saline injection at the corresponding time and recovered to the levels of the saline groups 6 h after injection (Fig. 8, A and B). The APAP-treated mice at 9:00 AM showed somewhat lower GSH levels than the lowest point of the 24-h rhythm of the untreated mice. On the other hand, hepatic GSH levels after APAP injection at 9:00 PM rapidly decreased to lower levels than the lowest point of the 24-h rhythm of the untreated mice. For the TRF group, hepatic GSH levels after APAP injection at 9:00 AM significantly decreased compared with those after saline injection at the corresponding time and recovered more than the levels of the saline groups 6 h after injection (Fig. 8C). On the other hand, the GSH of the APAP treated group at 9:00 PM was significantly lower from 30 min to 6 h after injection (Fig. 8D).
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Discussion |
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), this factor may be involved in the mechanisms underlying mortality induced by APAP. Feeding schedules control the overt phase of daily biological rhythm together with light-dark cycles (Boulos and Terman, 1980). In the present study, the time-restricted feeding schedule modified the rhythm of mortality and liver damage induced by APAP despite the light/dark condition.
APAP is mainly biotransformed and eliminated as non-toxic conjugates with glucuronic acid and sulfate (Nelson, 1995). In the case of APAP overdose, glucuronidation and sulfation are saturated, and APAP, which is not excreted from the body, increases along with the formation of NAPQI, a reactive toxic intermediate (Hjelle and Klaassen, 1984). NAPQI is formed by cytochrome P450 in the liver (Dahlin et al., 1984) and induces liver damage via a chain of cellular events. These events include depletion of cellular GSH and covalent binding to cellular proteins (Cohen and Khairallah, 1997), recruitment and activation of macrophages (Laskin and Pendino, 1995), initiation of oxidative stress and oxidation of protein thiols (Jaeschke, 1990; Tirmenstein and Nelson, 1990), alteration of calcium homeostasis, and damage to nuclear DNA (Corcoran and Ray, 1992).
In the present study on the ALF group, ALT activity and centrilobular necrosis after APAP (300 mg/kg, i.p.) injection at 9:00 PM were significantly more severe than those after injection at 9:00 AM. The covalent binding of NAPQI to liver cells 2 h after APAP injection was detected in centrilobular hepatocytes after injection at 9:00 PM but not after injection at 9:00 AM. Thus, the dosing time dependence of NAPQI covalent binding is one of mechanism that underlies chronohepatotoxicity induced by APAP. At least two forms of cytochrome P450, CYP2E1 and CYP1A2, are involved in the biotransformation from APAP to NAPQI. For example, the administration of ethanol and isoniazid, which are inducers of CYP2E1, potentiates APAP hepatotoxicity in animals (Burk et al., 1990; Prasad et al., 1990), and APAP hepatotoxicity is enhanced by chronic alcohol consumption in humans (Pezzano et al., 1988). In human studies, disulfiram, a CYP2E1-specific inhibitor, significantly reduces NAPQI formation (Hazai et al., 2002). CYP1A2-null, CYP2E1-null, and CYP1A2 and CYP2E1 double-null mice are significantly more resistant to APAP than wild-type mice (Gonzalez, 1998). In the present study, CYP2E1 levels for the ALF group varied with statistical significance over the course of 24 h. The rhythmicity of CYP2E1 activity corresponded to the dosing time dependence of NAPQI covalent binding. Taken together, these results suggest that CYP2E1 plays a key role in APAP bioactivation and hepatotoxicity.
Since NAPQI is detoxified by hepatic GSH, the rhythmicity of hepatic GSH levels may contribute to the hepatotoxicity induced by APAP. In the present study, a 24-h rhythm was observed for hepatic GSH levels for the ALF group. Higher GSH levels were observed when the liver damage of APAP decreased and vice versa. Thus, there was an inverse correlation between the rhythm of hepatic GSH levels and the rhythm of liver damage induced by APAP. These results suggest that the hepatic GSH levels at the injection time of APAP contribute to the amount of NAPQI detoxification. Likewise, the chronohepatotoxicity of chloroform and carbon tetrachloride (Skrzypinska-Gawrysiak et al., 1995, 2000) shows an inverse correlation with 24-h rhythmicity for hepatic GSH levels. For the ALF group, the reduction of hepatic GSH levels after APAP injection at 9:00 PM was greater than that after injection at 9:00 AM. The GSH levels at 30 min after APAP injection at 9:00 PM suddenly decreased to lower levels than the lowest point for the 24-h rhythm in untreated mice. Thus, the ability for GSH to conjugate with NAPQI and counteract it seems to be saturated and lost temporarily inhibited. On the other hand, GSH levels after APAP injection at 9:00 AM gradually decreased. Thus, these results suggest that a more rapid rate of production of NAPQI plays a role in hepatic damage after APAP.
The TRF group had a markedly different rhythm of CYP2E1 activity and GSH levels than that of the ALF group. For the groups in which little or no APAP adducts were immunohistochemically detected (ALF treated at 9:00 AM and TRF treated at 9:00 PM), the rapid depletion of GSH levels immediately after APAP injection was less severe. This can be explained by less formation of NAPQI under these conditions, which is also consistent with CYP2E1 activity. Accordingly, the most important effect of modulating feeding schedule may be the influence on CYP2E1 activity. Although the CYP2E1 activity and GSH levels for the ALF group varied with statistical significance over the course of 24 h, the levels varied more dramatically in the TRF mice. For the ALF group, CYP2E1 activity increased during the feeding period. Within the TRF group, CYP2E1 activity decreased during the feeding period and increased when food was with-held. TRF group mice that were injected with APAP at 9:00 PM started at slightly lower GSH levels than ALF mice and also showed values as low or lower, yet no signs of hepatic damage and low mortality were evident. TRF group mice only ate during the light phase. On the other hand, ALF group mice mostly ate during the dark phase and sometimes even during the light phase. Thus, the rhythmic pattern of feeding behavior was different between these groups. On the experimental day, food consumption by the TRF group was 15% lesser than that of the ALF group (ALF group, 6.150 ± 0.769 (n = 4, mean ± S.D.) g/mouse/day; TRF group, 5.183 ± 0.250 g/mouse/day). The temporary hunger state that time-restricted feeding induces raises the blood concentration of acetone and may give influence to CYP2E1 activity (Bruckner et al., 2002). Amino acids derived from food are available for the synthesis of GSH in the body (Deneke and Fanburg, 1989). Furthermore, the timing of drug administration and treatment may change the degree of food consumption and sleeping behavior during the mouse life cycle under ALF and TRF conditions. These factors may have underlined the different rhythmic patterns of several parameters between the ALF and TRF groups.
The suprachiasmatic nucleus (SCN) houses a master pacemaker that regulates behavioral and physiological circadian rhythms (Tei et al., 1997). Recently, clock genes have been identified, and several subsets of these genes seem to be under direct transcriptional control by internal molecular clocks (Reppert and Weaver, 2002). In addition, SCN communicates timing information to a variety of peripheral tissues via neural and humoral connections to help regulate fundamental physiological functions (Terazono et al., 2003). The manipulation of feeding schedule can modify rhythms such as locomotor activity, plasma corticosterone levels, and body temperature regardless of lighting schedule (Boulos and Terman, 1980), although lighting schedule is undoubtedly the most important factor in determining these rhythms. In addition, the 24-h rhythm of clock genes in other tissues excluding the SCN varies depending on feeding schedule (Damiola et al., 2000). In the present study, the manipulation of feeding schedule markedly modified the 24-h rhythm of CYP2E1 activity and GSH levels. Therefore, the 24-h rhythm of clock genes in other tissues excluding the SCN should be investigated as a mechanism that produces the 24-h rhythm of CYP2E1 activity and GSH levels in the liver.
The present study suggests that there was significant dosing time-dependent hepatotoxicity induced by APAP. The mechanism underlying this may be in part the rhythmicity of CYP2E1 activity and GSH conjugation. The present study also suggests that the time-dependent difference in mortality and hepatotoxicity induced by APAP associated with the rhythmicity of CYP2E1 activity and GSH conjugation were altered by repeated manipulation of the feeding schedule. Thus, this may control the chronopharmacological activity and chronopharmacokinetics of APAP by means of indirect food-drug interactions, which may be associated with endogenous oscillatory systems. Metabolism by cytochrome P-450 and GSH conjugation are common metabolic pathways for many drugs. These findings support the concept that choosing the most appropriate time of day to administer APAP associated with metabolic rhythmicity such as cytochrome P-450 and GSH conjugation may reduce hepatotoxicity in experimental and clinical situations.
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Footnotes |
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ABBREVIATIONS: APAP, acetaminophen; NAPQI, N-acetyl-p-benzoquinone imine; GSH, glutathione; ALF, ad libitum feeding; TRF, time-restricted feeding; ALT, alanineaminotransferase; PBS, phosphate-buffered saline; PNP, p-nitrophenol; SCN, suprachiasmatic nucleus.
Address correspondence to: Dr. Shigehiro Ohdo, Clinical Pharmacokinetics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail:ohdo{at}phar.kyushu-u.ac.jp
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) or TRF group (
). The number of deaths was recorded 7 days after drug injection. The values show the percentage for 10 mice. P < 0.01 when compared among the six different dosing times (
). B, APAP injection at 9:00 PM (
). C, for the TRF group, APAP injection at 9:00 AM (