Phenobarbital induction of hepatic CYP2B1 and CYP2B2: pretranscriptional and post-transcriptional effects of gender, adult age, and phenobarbital dose.
Chemical induction of hepatic monooxygenases should not be viewed as an extracorporal process but rather as one that is liable to be influenced by numerous endogenous factors. In this regard, we examined the interactions of gender, adult age, and barbiturate dose on the course of phenobarbital induction of hepatic CYP2B1 and CYP2B2. We observed that femaleness and youth were associated with the greatest inhibition, so that both the rate and initiation of CYP2B1 and CYP2B2 induction were suppressed most in the young adult (65 days of age) females, followed by the mature adult (150 days of age) females and then by the young adult males, with the mature adult males exhibiting the least suppression of phenobarbital induction. The differential expression rates of hepatic CYP2B1 mRNA in the young and mature male and female rats, similarly reflected at the protein level, suggest that gender- and age-dependent suppression of CYP2B1 occurs at a pretranscriptional or transcriptional level. In contrast, transcript levels of CYP2B2 were unaffected by gender or age. However, accumulation of cytochrome P450 (P450) 2B2 protein was affected by the animal's age and gender, suggesting regulation of a post-transcriptional event. Highly selective (androstenedione 16beta-hydroxylase) as well as nonspecific (total P450 and hexobarbital hydroxylase) P450 2B1- and 2B2-dependent catalytic activities were in agreement with protein levels. Determination of gender- and age-dependent circulating growth hormone profiles indicates that the continuous secretion of the hormone characteristic of the female is more suppressive of CYP2B induction than the episodic pattern growth hormone secretion found in males. The considerably elevated growth hormone pulse amplitudes observed in the young rats of both genders seem to be an additional inhibitory signal antagonizing phenobarbital induction of CYP2B1 and CYP2B2. Phenobarbital administration did not interfere with the normal gender- and age-dependent growth hormone secretory profiles. Last, although as little as 1 mg/kg phenobarbital increased CYP2B1 mRNA concentrations by 100%, there was no translation into detectable levels of protein. In contrast, the same low dose of barbiturate inducing an equal percent increase in CYP2B2 mRNA did result in an expression of protein. Unlike use of the 10 mg/kg dose, CYP2B1 and CYP2B2 induction by phenobarbital at 1 mg/kg was unaffected by age or gender.
Agrawal
A K
AK
Laboratories of Biochemistry, University of Pennsylvania School of Veterinary Medicine, Philadelphia, 19104-6048, USA.
Shapiro
B H
BH
D000367:Age Factors; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D015786:Cytochromes b5 / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D013006:Growth Hormone / Q000097:blood; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000096:biosynthesis / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013250:Steroid Hydroxylases / Q000096:biosynthesis* / Q000378:metabolism; D014158:Transcription, Genetic
D012333:RNA, Messenger; D013006:Growth Hormone; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C021352:hexobarbital hydroxylase; D001189:Aryl Hydrocarbon Hydroxylases; C025619:steroid 16-beta-hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase; D010634:Phenobarbital