Effects of huperzine A on liver cytochrome P-450 in rats
AIM: To predict possible drug interaction and assure safety medication of huperzine A (HupA). METHODS: The effects of HupA on activities and expressions of cytochrome P-450 (CYP) were examined. Liver microsomes and total mRNA were prepared from rats treated orally with 0, 0.1 (pharmacological dose), 1, or 2 mg/kg huperzine A for 2 weeks. Phenobarbital, 3-methylcholanthrene (3-MC), ethanol, and dexamethasone were used as positive controls. Total CYP protein was assayed by carbon monoxide difference spectrum. Activity of isoenzyme was detected with specific probe. Expression of CYP protein and mRNA was analyzed with Western blot and RT-PCR.
RESULTS: No changes of isoenzyme expression and catalytic activities were found in rats treated with 0.1 mg/kg huperzine A. Huperzine A 1, 2 mg/kg parallelly increased CYP1A2 activity, protein and mRNA, although they were minor when contrasted with 3-MC. Huperzine A 1, 2 mg/kg got no effects on CYP2C11, CYP2B1/2, 2E1 and 3A.
CONCLUSION: Activity and expression of liver CYP isoenzymes were not affected in rats treated with pharmacological dose of HupA, but HupA at toxicological dose may elicit a slight inductive response of CYP1A2. The CYP1A2 induction produced by HupA is related to transcription enhancement.
Acetylcholinesterase inhibitors (AChEI), such as physostigmine and tacrine, were identified to possess the action of ameliorating cognitive dysfunction of Alzheimer’s disease (AD). However, short duration of action, low bioavailability, frequent side effects, and dose-dependent hepatotoxicity limited their clinical values. New AChEI that has greater therapeutic window, longer duration of action, and fewer side ef-fects is desirable. Huperzine A (HupA) is a purified
compound derived from herb club moss (Huperziaserrata) found in China. It is a potent, reversible, and selective AChEI exhibiting memory-enhancing activities in animal and clinical trials. Compared with tacrineand physostigmine, HupA has a longer duration of action, higher therapeutic index and its peripheral cholinergic side effects are minimal at therapeutic doses.
Treatment for AD patients with HupA needs a long course and combined medications are often required. Combining and successive medications are the common reasons for inhibition or induction of cytochrome P-450 (CYP) and adverse drug reaction may thus occur. It is necessary to identify the effects of HupA on CYP expression, which will be beneficial for understanding the consequences of pharmacology, toxicology, and therapeutics of HupA and other combined drugs
, while limited data are available about effects of HupA on liver CYP up to now. Present study was attempted to examine the effects of HupA on liver CYP to indicate possible drug interactions and avoid possible adverse drug reactions.
In the present study, decreases of liver microsomal protein and total CYP were noted in rats treated with HupA 2 mg/kg. Liver microsomal protein and total CYP levels are always related to liver functional status, such as blood and oxygen supply, which can be interfered by AChEI. Over dose of AChEI increases ACh at the celiac ganglion and thus increases sympathetic activity via the hepatic nerve. When ACh is released in the celiac ganglion and causes an action potential that propagates through the hepatic nerve, sinusoidal vascular space and tissue perfusion will bedecreased. For rats, HupA 0.1 mg/kg is a pharmacological dose[, and 2 mg/kg is 20 times of pharmacological dose. It is suspected that overdoses of HupA affect liver functional status and decrease microsomal protein and total CYP.
Significant increases of CYP1A2 activity and protein were consistent with the increase of CYP1A2 mRNA, which indicate that the induction produced by HupA is related to transcription enhancement, while the induction produced by HupA 2 mg/kg was minor in contrast with 3-MC, a generally accepted CYP1A2 inducer. Interestingly, HupA-induced CYP1A2 expression was not paralleled by total CYP increase. On adverse, a reduction in total CYP was found in rats treated with HupA 2 mg/kg, which suggests that only total CYP may not always be adequate to indicate enzyme induction, especially when the extent of induction is weak.
The therapeutic doses of HupA in human should not be high enough to elicit an induction response of CYP1A2. CYP1A2, about 13 % of total CYP isoenzymes in human liver, is an enzyme with both pharmacologic and toxicologic significance, which involves metabolic clearance of many drugs and has been implicated in the metabolic activation of certain procarcinogens and promutagens. CYP1A2 activity can be induced by environmental factor like smoking and caffeinated drinks, and some drugs, such as insulin and modafinil. At the same time, CYP1A2 activity can be inhibited by other drugs, such as cimetidine, methoxsalen, quinolones, furafylline, citalopram, fluoxetine, fluvoxamine, and moclobemide. So doctors of AD patients should pay attention to the factors interfering CYP1A2 to avoid possible drug interactions and assure safety of HupA medication.
In conclusion, activity and expression of liver CYP were not affected in rats treated with pharmacological dose of HupA, but at toxicological dose of HupA may elicit a slight inductive response of CYP1A2. The CYP1A2 induction produced by HupA is related to transcription enhancement. Because CYP1A2 is involved in the metabolism of numerous important drugs, further studies are required to assess whether HupA causes a clinically relevant interaction with any CYP1A2 substrates and/or inhibitors.
RESULTS: No changes of isoenzyme expression and catalytic activities were found in rats treated with 0.1 mg/kg huperzine A. Huperzine A 1, 2 mg/kg parallelly increased CYP1A2 activity, protein and mRNA, although they were minor when contrasted with 3-MC. Huperzine A 1, 2 mg/kg got no effects on CYP2C11, CYP2B1/2, 2E1 and 3A.
CONCLUSION: Activity and expression of liver CYP isoenzymes were not affected in rats treated with pharmacological dose of HupA, but HupA at toxicological dose may elicit a slight inductive response of CYP1A2. The CYP1A2 induction produced by HupA is related to transcription enhancement.
Acetylcholinesterase inhibitors (AChEI), such as physostigmine and tacrine, were identified to possess the action of ameliorating cognitive dysfunction of Alzheimer’s disease (AD). However, short duration of action, low bioavailability, frequent side effects, and dose-dependent hepatotoxicity limited their clinical values. New AChEI that has greater therapeutic window, longer duration of action, and fewer side ef-fects is desirable. Huperzine A (HupA) is a purified
compound derived from herb club moss (Huperziaserrata) found in China. It is a potent, reversible, and selective AChEI exhibiting memory-enhancing activities in animal and clinical trials. Compared with tacrineand physostigmine, HupA has a longer duration of action, higher therapeutic index and its peripheral cholinergic side effects are minimal at therapeutic doses.
Treatment for AD patients with HupA needs a long course and combined medications are often required. Combining and successive medications are the common reasons for inhibition or induction of cytochrome P-450 (CYP) and adverse drug reaction may thus occur. It is necessary to identify the effects of HupA on CYP expression, which will be beneficial for understanding the consequences of pharmacology, toxicology, and therapeutics of HupA and other combined drugs
, while limited data are available about effects of HupA on liver CYP up to now. Present study was attempted to examine the effects of HupA on liver CYP to indicate possible drug interactions and avoid possible adverse drug reactions.
In the present study, decreases of liver microsomal protein and total CYP were noted in rats treated with HupA 2 mg/kg. Liver microsomal protein and total CYP levels are always related to liver functional status, such as blood and oxygen supply, which can be interfered by AChEI. Over dose of AChEI increases ACh at the celiac ganglion and thus increases sympathetic activity via the hepatic nerve. When ACh is released in the celiac ganglion and causes an action potential that propagates through the hepatic nerve, sinusoidal vascular space and tissue perfusion will bedecreased. For rats, HupA 0.1 mg/kg is a pharmacological dose[, and 2 mg/kg is 20 times of pharmacological dose. It is suspected that overdoses of HupA affect liver functional status and decrease microsomal protein and total CYP.
Significant increases of CYP1A2 activity and protein were consistent with the increase of CYP1A2 mRNA, which indicate that the induction produced by HupA is related to transcription enhancement, while the induction produced by HupA 2 mg/kg was minor in contrast with 3-MC, a generally accepted CYP1A2 inducer. Interestingly, HupA-induced CYP1A2 expression was not paralleled by total CYP increase. On adverse, a reduction in total CYP was found in rats treated with HupA 2 mg/kg, which suggests that only total CYP may not always be adequate to indicate enzyme induction, especially when the extent of induction is weak.
The therapeutic doses of HupA in human should not be high enough to elicit an induction response of CYP1A2. CYP1A2, about 13 % of total CYP isoenzymes in human liver, is an enzyme with both pharmacologic and toxicologic significance, which involves metabolic clearance of many drugs and has been implicated in the metabolic activation of certain procarcinogens and promutagens. CYP1A2 activity can be induced by environmental factor like smoking and caffeinated drinks, and some drugs, such as insulin and modafinil. At the same time, CYP1A2 activity can be inhibited by other drugs, such as cimetidine, methoxsalen, quinolones, furafylline, citalopram, fluoxetine, fluvoxamine, and moclobemide. So doctors of AD patients should pay attention to the factors interfering CYP1A2 to avoid possible drug interactions and assure safety of HupA medication.
In conclusion, activity and expression of liver CYP were not affected in rats treated with pharmacological dose of HupA, but at toxicological dose of HupA may elicit a slight inductive response of CYP1A2. The CYP1A2 induction produced by HupA is related to transcription enhancement. Because CYP1A2 is involved in the metabolism of numerous important drugs, further studies are required to assess whether HupA causes a clinically relevant interaction with any CYP1A2 substrates and/or inhibitors.