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Lack of inducibility of brain monooxygenase activities including parathion desulfuration
1Department of Biological Sciences, Mississippi State University 39762.
Abstract:
The ability of phenobarbital and beta-naphthoflavone to induce parathion desulfuration, aminopyrine N-demethylation, and NADPH-cytochrome-c reductase activity in the brain and liver of male and female rats was investigated. Activities of all three enzymes were found in similar levels in both the mitochondrial and microsomal fractions of brain. There were no sex differences in brain activities. Liver activities were from 10- to 30-fold higher than brain activities when computed on a tissue-wet-weight-equivalent basis. Although exposure to both inducers increased all three enzyme activities and cytochrome P-450 in liver, neither inducer increased the enzyme activities in mitochondrial or microsomal brain fractions of either sex. Thus, these brain monooxygenase activities appear to be refractory to induction by two classical types of cytochrome P-450 inducers. This lack of inducibility could serve to protect the animal against environmentally enhanced increases in the activation of xenobiotics to neurotoxic metabolites, such as parathion desulfuration to paraoxon.
Insights
Brain enzymes involved in detoxifying foreign compounds, like parathion, do not increase when exposed to common inducers. This natural refractoriness may protect the brain from harmful neurotoxic metabolites.
Area of Science:
- Biochemistry
- Toxicology
- Neuroscience
Background:
- Liver enzymes, including cytochrome P-450, are crucial for metabolizing xenobiotics.
- Phenobarbital and beta-naphthoflavone are known inducers of these liver enzymes.
- Brain monooxygenase activities are less understood regarding their inducibility.
Purpose of the Study:
- To investigate the inducibility of parathion desulfuration, aminopyrine N-demethylation, and NADPH-cytochrome-c reductase in rat brain and liver.
- To determine if sex influences these enzyme activities or their induction.
- To assess the brain's response to classical cytochrome P-450 inducers.
Main Methods:
- Enzyme activities were measured in mitochondrial and microsomal fractions of rat brain and liver.
- Rats were exposed to phenobarbital and beta-naphthoflavone.
- Enzyme assays included parathion desulfuration, aminopyrine N-demethylation, and NADPH-cytochrome-c reductase.
- Cytochrome P-450 levels were also assessed.
Main Results:
- Brain enzyme activities were similar in mitochondrial and microsomal fractions, with no sex differences.
- Liver enzyme activities were significantly higher (10-30 fold) than brain activities.
- Neither phenobarbital nor beta-naphthoflavone induced the measured enzyme activities or cytochrome P-450 in brain fractions.
- Both inducers significantly increased enzyme activities and cytochrome P-450 in liver.
Conclusions:
- Rat brain monooxygenase activities are refractory to induction by phenobarbital and beta-naphthoflavone.
- This lack of inducibility may represent a protective mechanism against neurotoxic metabolite formation.
- The brain's detoxification pathways exhibit a distinct regulation compared to the liver.