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

Abstract

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...

Metabolism of a Heterocyclic Amine Colon Carcinogen in Young and Old Rats

“…However, at the protein level, there was no difference in the maximal levels of P450 protein induced as a function of age (Horbach et al, 1992). In another study, low doses of pentobarbitol showed no effect of age in terms of inducing a whole range of hepatic P450s (Agrawal and Shapiro, 2003). The capacity of TCDD to induce some forms of P4501A either remained unchanged or increased with age (Pegram et al, 1995).…”

Energy Restriction Does Not Compensate for the Reduced Expression of Hepatic Drug-Processing Genes in Mice with Aging

“…ER has been shown to exert various beneficial effects in attenuating aging and age-related diseases (Anderson and Weindruch, 2007;Anderson et al, 2009). However, studies of ER effects on liver functions are either general, such as the whole genome profiling of hepatic gene expression (Cao et al, 2001), or focus on energy metabolism, such as glucose metabolism (Hagopian et al, 2003), or several specific drug-metabolizing enzymes (Agrawal and Shapiro, 2003). The current study was designed to reveal how aging influences the hepatic drug-processing system and whether long-term ER can counteract the changes caused by aging.…”

“…Although little reduction was observed in the activity of most P450 isoforms in aged male rats, the male-dominant Cyp2c11 isoform decreased ϳ70% in mRNA, protein, and catalytic activity between 5 and 23 months of age (Agrawal and Shapiro, 2003). Because Cyp2c11 comprises approximately 50% of total hepatic P450s in male rats, a dramatic decrease in drug-processing capacity would be expected in aged male rats.…”

“…Low-dose phenobarbital treatments (1 and 10 mg/kg) induced the expression of Cyp2b1, Cyp2b2, and Cyp3a1 to the same degree in young and aged rats (Agrawal and Shapiro, 2003). However, exposure to toluene (1 g/kg) decreased the transcription of more phase II enzymes and efflux transporters in 24-month-old rats than in 4-month-old rats (Lee et al, 2008).…”

Ontogeny of Hepatic and Plasma Metabolism of Deltamethrin in Vitro: Role in Age-Dependent Acute Neurotoxicity

“…Whereas reports on developmental changes (Gebremichael et al, 1995;Atterberry et al, 1997) of CYP1A1/2 and CYP2B1/2 activities are contradictory, ontogeny of DLM metabolism (Table 1) is not in accordance with the developmental changes of these enzymes. The possible reasons could be that 1) ethoxyresorufin O-deethylase and pentoxyresorufin O-dealkylase are usually considered to be catalyzed by CYP1A1/2 and CYP2B1/2, respectively, but other P450s (i.e., CYP2C6 and 2C11) also contribute to deethylase and dealkylase activities (Kobayashi et al, 2002); and 2) there is no consensus on constitutive protein expression of CYP1A1/2 and CYP2B1/2 in rats (de Waziers et al, 1990;Agrawal and Shapiro, 2003).…”