Androgenic repression of hexobarbitone metabolism and action in Crl:CD‐1 (ICR)BR mice

Shapiro, Barry A.; Szczotka, Susan M.

doi:10.1111/j.1476-5381.1984.tb10742.x

Cited by 25 publications

(6 citation statements)

References 13 publications

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“…Multi-P450-dependent microsomal hexobarbital hydroxylase, mostly catalyzed by male-specific CYP2C11 and CYP2C13, less so by female-dependent CYP2C6 and CYP2C12 as well as by CYP2B1 and CYP2B2 in phenobarbital-treated rats (Ryan and Levin, 1990), was measured as reported in Shapiro and Szczotka (1984).…”

Section: Methodsmentioning

confidence: 99%

Constitutive and Inducible Hepatic Cytochrome P450 Isoforms in Senescent Male and Female Rats and Response to Low-Dose Phenobarbital

Agrawal

Shapiro²

2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Numerous studies, usually limited to male rodents, have reported an inverse relationship between the age of the animal and the activities of various multi-cytochrome P450-dependent drug-metabolizing enzymes. It has been suggested that the aging-induced decline in hepatic drug-metabolizing capacity is solely a male phenomenon. That is, whereas the levels of male-specific isoforms of P450 decline with senescence, the female-dependent isoforms remain unchanged in females and even increase in male liver. In addition to their baseline activities, induction levels of hepatic monooxygenases have also been reported to decrease with aging. To examine aging-and sex-dependent effects on drug metabolism at a more molecular level, we measured the expression (mRNA, protein, and/or catalytic activity) of a near dozen constitutive and inducible isoforms of P450 in 5-and 23-month-old male and female Sprague-Dawley rats. Moreover, we investigated the induction effects of low concentrations of phenobarbital known to reveal gender differences and the threshold sensitivities of both constitutive and inducible isoforms. With the exception of male-specific CYP2C11 (whose expression declined ϳ70% in aged male rats), we observed little senescence-associated reduction in either preinduction or induction levels of CYP2B1, CYP2B2, CYP3A1, CYP3A2, CYP2C6, CYP2C7, CYP2C12, and CYP2C13 in either male or female rats. Moreover, the sexually dimorphic expression levels apparent at 5 months of age persisted in the old rats.People over 65 years of age represent the fastest growing segment of the population and consume at least one-third of all prescription drugs. Stated another way, 82% of people over 65 use prescription medications (Willcox et al., 1994). Moreover, the high prevalence of polypharmacy in the elderly likely contributes to an abnormally high 20 to 25% incidence of adverse drug reactions and toxicities in this age group (Hunt et al., 1992;Willcox et al., 1994). The generally accepted aging-associated decline in drug disposition is a result of senescent changes in drug absorption, distribution, excretion, and/or metabolism (Schmucker and Lonergan, 1987). Direct studies on liver drug metabolism in elderly humans are scant with most evidence derived from animal studies.In this regard, early investigations using laboratory animals had to limit their analyses to nonspecific multi-P450 2 -dependent drug-metabolizing enzymes. Moreover, the important contribution of sex was often overlooked by using only the "preferred" gender in pharmacotoxicological studies, the male rodent, or worse yet, not even recording the sex of the animal. Last, few investigators considered the effect of strain, a critical factor (Chengelis, 1988) influencing age-associated changes in drug metabolism.One of the earliest studies using rats reported an inverse relationship between age and the metabolism of commonly used model substrates (Kato and Takanaka, 1968). This, as well as additional stud...

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Section: Methodsmentioning

confidence: 99%

Constitutive and Inducible Hepatic Cytochrome P450 Isoforms in Senescent Male and Female Rats and Response to Low-Dose Phenobarbital

Agrawal

Shapiro²

2003

Drug Metab Dispos

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“…Prolonged sleeping times are undoubtedly due to a commensurate decline in hexobarbital hydroxylase activity (Shapiro and Szczotka, 1984;Pampori et al, 1991b). Since microsomal hexobarbital hydroxylase represents the contributing activities of several isoforms of P450, of which CYP2C11 and CYP3A2 are dominant (Ryan and Levin, 1990), we determined the expression levels of these male-specific P450s in our animals.…”

Section: Resultsmentioning

confidence: 99%

Prevention of Latently Expressed CYP2C11, CYP3A2, and Growth Hormone Defects in Neonatally Monosodium Glutamate-Treated Male Rats by theN-Methyl-d-Aspartate Receptor Antagonist Dizocilpine Maleate

Kaufhold

Nigam²,

Dhir³

et al. 2002

J Pharmacol Exp Ther

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Neonatal administration of monosodium glutamate (MSG) can produce latently expressed defects in drug metabolism and growth hormone secretion as well as stunted growth and obesity. Instead of secreting growth hormone in the masculine episodic profile, plasma hormone levels are generally undetectable in affected adult male rats. Moreover, male-specific isoforms of cytochrome P450 (P450; e.g., CYP2C11 and CYP3A2), whose combined levels comprise the bulk of the total hepatic P450 in adult male rats, are similarly undetectable in these animals. Since "signaling elements" in the masculine episodic growth hormone profile are solely responsible for the elevated characteristic malelike expression levels of CYP2C11 and CYP3A2, suppression of the isoforms in the MSG-treated rats appeared to be caused by the simple absence of the hormone from the circulation. However, the reported failures of restored physiologic masculine growth hormone profiles to correct the P450 defects suggested the occurrence of direct MSG-induced liver damage independent of the well known hypothalamic lesions produced by the amino acid. Concurrent administration of dizocilpine maleate (MK-801), a selective and highly potent noncompetitive N-methyl-D-aspartate receptor antagonist of glutamate, completely prevented the adverse effects of neonatal MSG treatment on P450 expression, growth hormone secretion, and growth parameters, indicating that the amino acid-induced defects are solely a result of neuronal (i.e., hypothalamic) damage produced at the time of MSG exposure. The irreversibility of the P450 damage is described as resulting from secondary defects initially induced by the neuronal lesions.

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“…Hepatic microsomes and cytosol were prepared using a differential ultracentrifugation method (Shapiro and Szczotka, 1984). The resulting microsomal pellet was suspended in pH 7.4 buffer (50 mM Tris and 0.25 M sucrose), and stored at Ϫ80°C.…”

Section: Methodsmentioning

confidence: 99%

Effect of Perinatal Low Protein Diets on the Ontogeny of Select Hepatic Cytochrome P450 Enzymes and Cytochrome P450 Reductase in the Rat

Cherala¹,

Shapiro²,

D’mello³

2007

Drug Metab Dispos

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ABSTRACT:In the present study, we administered two low protein diets (LPDs) to rats during pregnancy and lactation and determined their effect on the ontogeny of select hepatic cytochrome P450 (P450) isoforms in their offspring. The L93 and LM76 LPDs were derived from the American Society of Nutrition recommended AIN93G and a modified version of the AIN76A purified control diets, respectively. The LPDs contained 8% crude protein in the form of casein, whereas the purified control diets contained 19% casein. A regular cereal-based diet (NP) was also included, and, therefore, a total of five groups were tested. Pups in all five groups were weaned onto a regular NP diet on postnatal day 28. Perinatal LPD altered the activities of a number of P450 isoforms in 28-day-old male and female offspring. However, nutritional rehabilitation abolished most of these changes as evidenced by lack of differences between the five groups in the activities of P450 isoforms in either 65-or 150-day-old offspring. Interestingly, 58-day-old female offspring in the LM76 group but not those in the L93 group exhibited shorter hexobarbital sleep time than the purified control group. However, hexobarbital hydroxylase activity and the amount of CYP2C12 protein, an important P450 isoform involved in hexobarbital metabolism in females, were unchanged. This suggests that the decrease in hexobarbital sleep time in this group is not due to an increase in the activity of hexobarbital-metabolizing enzymes. In summary, perinatal LPDs produced transient alterations in activities of select hepatic P450s and resulted in a gender-and diet-dependent longterm alteration in hexobarbital pharmacodynamics.Cytochrome P450 (P450) is a superfamily of membrane-bound enzymes involved in metabolism of endogenous and exogenous compounds. P450s are present in many organs including the liver, kidney, spleen, adrenal glands, and intestine. The hepatic P450s are known to exhibit zonal expression (Oinonen and Lindros, 1998), with most P450s exhibiting a predominantly perivenous zonation. P450 expression is regulated by hormones such as insulin, thyroid hormone, and growth hormone (Schenkman and Griem, 1993).Epidemiological studies demonstrate a strong association between low birth weight and high incidence of ischemic heart disease, elevated systolic blood pressure, impaired glucose tolerance, and syndrome X during adulthood (Barker et al., 1993). To study the association in more mechanistic detail, a variety of animal models of intrauterine growth restriction have been developed. A commonly used model involves the administration of low protein diets to rats during the pregnancy and lactation (perinatal) period. There are striking similarities between this model and the epidemiological findings. Maternal low protein diets during pregnancy and lactation decrease birth weight in the pups and result in poor glucose tolerance, hyperlipidemia, and hypertension in the adult offspring.A careful review of the literature reveals two effects of perinatal low protein diets that are...

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Androgenic repression of hexobarbitone metabolism and action in Crl:CD‐1 (ICR)BR mice

Cited by 25 publications

References 13 publications

Constitutive and Inducible Hepatic Cytochrome P450 Isoforms in Senescent Male and Female Rats and Response to Low-Dose Phenobarbital

Constitutive and Inducible Hepatic Cytochrome P450 Isoforms in Senescent Male and Female Rats and Response to Low-Dose Phenobarbital

Prevention of Latently Expressed CYP2C11, CYP3A2, and Growth Hormone Defects in Neonatally Monosodium Glutamate-Treated Male Rats by theN-Methyl-d-Aspartate Receptor Antagonist Dizocilpine Maleate

Effect of Perinatal Low Protein Diets on the Ontogeny of Select Hepatic Cytochrome P450 Enzymes and Cytochrome P450 Reductase in the Rat

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