Divergent regulation of cytochrome P450 enzymes by morphine and pethidine: a neuroendocrine mechanism?
We have studied the effects of opiates on cytochrome P450 (CYP) expression in rats and, intriguingly, found that these compounds have divergent effects on this system. Morphine induced a selective down-regulation of hepatic 16 alpha-hydroxylation of androstenedione, which was associated with a reduction in the expression of the 16 alpha-hydroxylation-associated CYP2C11. In addition, other enzymes from the CYP2C, CYP3A, and CYP4A gene families were also suppressed, whereas CYP1A2, CYP2B1, and CYP2E1 were induced. These changes were reflected in the mRNA levels, indicating that they were due to alterations at the transcriptional level. alpha 2-Adrenoceptor blockade with yohimbine augmented the effects of morphine on proteins identified by antibodies against CYP2C11 and CYP3A, indicating an involvement or influence of the alpha 2-adrenergic receptor system. In contrast, pethidine had completely different effects. No CYPs were suppressed by this compound. CYP1A2, CYP2B1, CYP2C6, CYP2C7, CYP3A, and CYP4A1 were all induced by pethidine treatment, whereas CYP2C11 and CYP2E1 were unchanged. Our results demonstrate for the first time the divergent effects of pethidine and morphine on the hepatic CYP system, indicating that an opioid receptor mechanism is not involved. These differences are probably mediated by different influences on growth hormone secretion. The mechanisms by which this may occur are discussed.
Department of Clinical Pharmacology, Akademiska Hospital, Uppsala University, Sweden.
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A
Rane
Z
Z
Liu
C J
CJ
Henderson
C R
CR
Wolf
D000311:Adrenal Glands / Q000187:drug effects / Q000201:enzymology; D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D003000:Clonidine / Q000494:pharmacology; D003350:Cortodoxone / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D003900:Desoxycorticosterone / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects*; D007527:Isoenzymes / Q000187:drug effects* / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008614:Meperidine / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009020:Morphine / Q000494:pharmacology*; D009490:Neurosecretory Systems / Q000187:drug effects* / Q000201:enzymology*; D011374:Progesterone / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase; D013256:Steroids / Q000378:metabolism; D015016:Yohimbine / Q000494:pharmacology
D007527:Isoenzymes; D012333:RNA, Messenger; D013256:Steroids; D015016:Yohimbine; D000735:Androstenedione; D003900:Desoxycorticosterone; D011374:Progesterone; D009020:Morphine; D003577:Cytochrome P-450 Enzyme System; D008614:Meperidine; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D003000:Clonidine; D003350:Cortodoxone