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Nominal Growth Hormone Pulses in Otherwise Normal Masculine Plasma Profiles Induce Intron Retention of Overexpressed Hepatic CYP2C11 with Associated Nuclear Splicing Deficiency¹

Laboratories of Biochemistry, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104-6048

Address all correspondence and requests for reprints to: Dr. Bernard H. Shapiro, Laboratories of Biochemistry, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, Pennsylvania 19104-6048. E-mail: shapirob{at}vet.upenn.edu

Restoration of circulating masculine GH profiles at minipulse amplitudes (i.e. 10% of normal) to hypophysectomized male rats and neonatal administration of monosodium glutamate (MSG), producing a similar plasma GH profile, both result in an overexpression (200–300%) of CYP2C11 messenger RNA (mRNA), the predominant hepatic cytochrome P450 (CYP) drug-metabolizing enzyme in adult male rats. Coincident with the severalfold elevation in transcript level is a modest 10–30% overexpression of CYP2C11 protein and its catalytic activities. Using hepatic tissue from adult, neonatally MSG-treated rats, we have cloned a variant species of CYP2C11 mRNA containing all of the essential elements of a full-length complementary DNA, including initiating codon, termination codon, and polyadenylase tail. In addition, the transcript contains a 742-bp intervening sequence (identical to the complete terminal intron) between the last and penultimate exons, and an intron-specific oligo probe for Northern blotting demonstrates the presence of the variant transcript in liver of MSG-treated rats. Associated with the overexpression and intron retention of the transcript is a 50% reduction in the nuclear splicing capacity of the liver for model precursor CYP2C11 mRNA. It is proposed that this splicing defect may be a consequence of the mini-GH pulses (secreted in otherwise normal masculine plasma profiles) signaling abnormal processing of precursor CYP2C11 mRNA to produce a substantial portion of intron retained, nontranslatable transcript.

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