Influence of aging and induction on rat liver and kidney microsomal mixed function oxidase systems

McMartin, Donald N.; O'Connor, James A.; Fasco, Michael J.; Kaminsky, Laurence S.

doi:10.1016/0041-008x(80)90168-4

Cited by 67 publications

(11 citation statements)

References 25 publications

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“…This, as well as additional studies observed an aging related decline in the in vivo and in vitro metabolism of different classes of drugs, subnormal baseline concentrations of various components of the hepatic drug-metabolizing enzyme system, and/or a decrease in the rate and extent of monooxygenase induction by several agents (Birnbaum and Baird, 1978;McMartin et al, 1980;Schmucker and Wang, 1981). However, there have been numerous conflicting reports indicating no senescent-induced changes in both drug-metabolizing enzyme activities or in their response to inducing agents (Adelman, 1971;Kao and Hudson, 1980;Chengelis, 1988).…”

mentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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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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mentioning

confidence: 94%

Section: Introductionmentioning

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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“…Schematic representation showing the various levels of induction of cytochrome P450 enzymes. reported either a decrease [39,[77][78][79] or no change [80] in the extent of monooxygenase induction by several agents. (Fig.…”

Section: B Effect Of Ageing On the Capacity Of Cytochrome P450 Enzymmentioning

confidence: 99%

The Effect of Ageing on Cytochrome P450 Enzymes: Consequences for Drug Biotransformation in the Elderly

Wauthier¹,

Verbeeck

Calderón

2007

CMC

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Abstract:Ageing is an aggravating factor leading to alterations in the biotransformation of drugs, and therefore their therapeutic efficacy and safety. In this review we discuss the influence of ageing on drug metabolizing enzymes in male Wistar rats. We report that drug metabolizing enzymes can be affected by ageing either by post-translational modifications or by transcriptional modifications. The post-translational modifications could be due to an increase of oxidative stress during ageing. Although it is now well established that transcriptional modifications are due to a change in the GH secretion profile in senescent rats, the intracellular mechanisms underlying these modifications are still unclear. In addition to the strong decrease in the activity of the main CYPs of male rats, we discuss the potential consequences on human drug metabolism in the elderly.

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“…The activities of the hepatic microsomal mixed function oxidases are low at birth, increasing with age and reach maximum levels usually within a few weeks (Jondorf et al, 1959;Basu et al, 1971;loannides et al, 1977). However, the levels of enzyme activity start declining again as the animal approaches old age (Kato & Takanaka, 1968;McMartin, O'Connor, Fasco & Kaminsky, 1980;Rikans & Notley, 1981).…”

Section: Discussionmentioning

confidence: 99%

“…However, the levels of enzyme activity start declining again as the animal approaches old age (Kato & Takanaka, 1968;McMartin, O'Connor, Fasco & Kaminsky, 1980;Rikans & Notley, 1981).…”

Section: Resultsmentioning

confidence: 99%

Elimination of Glyceryl Trinitrate: Effects of Sex, Age, Species and Route of Administration

Ioannides

Parke

Taylor

1982

British J Pharmacology

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Orally administered glyceryl trinitrate to rats undergoes extensive first pass metabolism leading to low bioavailability. Sex differences in the plasma elimination of glyceryl trinitrate were seen in the rat, the female exhibiting the longer plasma half‐life. No sex differences in this respect were detected in the rabbit. The plasma half‐life of glyceryl trinitrate was longer and the volume of distribution larger, in older animals. The plasma elimination of glyceryl trinitrate was different in various animal species. There was a good correlation between plasma half‐life and animal bodyweight.

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Influence of aging and induction on rat liver and kidney microsomal mixed function oxidase systems

Cited by 67 publications

References 25 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

The Effect of Ageing on Cytochrome P450 Enzymes: Consequences for Drug Biotransformation in the Elderly

Elimination of Glyceryl Trinitrate: Effects of Sex, Age, Species and Route of Administration

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