Variation in the activity of liver microsomal drug-metabolizing enzymes in rats in relation to the age

Kato, Ryuichi; Vassanelli, P; Frontino, G.; Chiesara, E.

doi:10.1016/0006-2952(64)90100-5

Cited by 267 publications

(76 citation statements)

References 9 publications

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“…A drastic decline in P-450 functions with age reported in male rats as early as in the sixties (Kato et al 1964) has long been taken as an experimental basis for the possible decline in hepatic drug metabolism in the elderly (Kitani 1988). However, it is my tentative conclusion that for a majority of drugs metabolized by the liver, their clearance values are not altered with age per se, especially when clearance values are corrected for liver volume.…”

Section: What Really Declines With Age?mentioning

confidence: 99%

What really declines with age?

Kitani¹

2007

AGE

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In order to understand the basic mechanisms underlying the organismic aging process, considerable efforts have been devoted in the last half-century to biochemical (enzyme activity) alterations in specific tissues and organs of various organisms associated with aging. When a decline in enzyme activities with age has been found in a study, especially for key enzymes such as antioxidant enzymes, the results have often been interpreted as a cause for the aging of the entire body. Retrospectively, however, these changes turned out to be so variabledepending on species, strains and sexes of animalsthat the interpretation of these results in general terms of aging became invalid. Further, unlike the prediction for the whole human body, many enzyme activities in a vital organ, such as the liver, remained unchanged, as long as the old subjects remained healthy. However, enzyme activities in old animals and humans are often more susceptible to morbidities and frailties, which themselves are often accompanied by infections and malnutrition. Despite the rather stable enzyme functions in the liver with age, a distinct and progressive decline in the lateral diffusion coefficient of proteins of hepatocyte plasma membranes has been demonstrated by fluorescence recovery after photobleaching (FRAP), which was implicated as the cause for the decline of hepatocyte functions such as ouabain (and taurocholate) hepatic uptake and their eventual biliary excretion. Since a similar decline in protein diffusion coefficients was observed in brain and muscle cells, it is likely that these changes are occurring in common with many cell types of the body, thus causing a delay in transmembrane transport of endogenous and exogenous substances whose transports are mediated by membrane proteins. In attempts to prolong the life spans of animals other than by calorie restriction, but instead using deprenyl or tetrahydrocurcumin, works by the author and coworkers are introduced and discussed. Despite limited success along these lines thus far, further attempts are encouraged, primarily to understand the mechanisms underlying organismic aging processes and to find a practical way to prolong the health span of the elderly.

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Section: What Really Declines With Age?mentioning

confidence: 99%

What really declines with age?

Kitani¹

2007

AGE

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“…3. Activities of NADPH oxidase, NADPH-cytochrome c reductase and NADPH neotetrazolium diaphorase and amounts of cytochrome b5 and P-450 in male and female rats bearing Walker 256 carcinosarcoma Since the alternations in the activities of drug-metabolizing enzymes were often relat ed to the alternations in the activities of NADPH-dependent electron transport system of liver microsomes (5,12,16,(32)(33)(34)(35)(36), the activities of NADPH oxidase , NADPH-cytochrome c reductase and NADPH-neotetrazolium diaphorase and the amounts of cytochrome b5 and P-450 in the male and female rats bearing Walker 256 carcinosarcoma were investigated . Average tumor weight per 100 g body weight was about 11.9 g and 3.6 g, respectively, in the large tumor bearing rats and small tumor-bearing rats .…”

Section: Fig 1 Activities Of Pentobarbital Oxidase Carisoprodol Oxmentioning

confidence: 99%

Drug Metabolism in Tumor-Bearlng Rats

Kato

Takanaka

Takahashi

et al. 1968

Japanese Journal of Pharmacology

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It has recently been recognized that the metabolism of lipid soluble compounds by liver microsomal enzymes is highly important factors for controlling the action and toxicity of various drugs (1-5). This fact is, especially, important for some drugs which should be converted to the active metabolite in vivo (5-7). Some carcinogenic and carcinostatic compounds, such as dimethylnitrosamine, 2-acethylaminofluorene, 4-nitroquinoline N oxide and cyclophosphoramide, belong to this group (8-11).The activities of drug-metabolizing enzymes of liver microsomes are markedly altered by several factors, such as, the administrations of different kind of lipid soluble compounds and anabolic hormones, starvation, low protein diet, formaline and adrenaline stress, al loxan diabetes, hyperthyroidism, adrenalectomy, viral hepatitis and hepatectomy (1,3,(12)(13)(14)(15)(16)(17)(18)(19)(20).In a preliminary work,* we observed a decrease in the metabolism of pentobarbital, meprobamate and strychnine in Walker 256 carcinosarcoma bearing male rats. How ever, there are clear sex difference in the alternation of activities of drug-metabolizing enzymes by the non-physiological conditions. For example, starvation, formalin and ad renaline stress, alloxan diabetes, hyperthyroidism and adrenalectomy markedly decrease the activities of most of the enzymes in male rats, while they did not significantly alter or rather increased the activities in female rats (13,14).It would be, thus, interesting to investigate whether the decrease in the metabolism of drugs by liver microsomes of the tumor-bearing rats is only limited to male rats. Moreover, whether the activities of other drug-oxidizing enzymes, drug-reducing enzymes and electron transport systems is affected or not by tumor-bearing was investigated.Furthermore, in order to obtain some insights in the mechanism of decrease in the activities of drug-metabolizing enzymes in tumor-bearing rats, the effect of phenobarbital treatment on these enzyme activities in control rats and tumor-bearing rats was compara tively investigated.

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“…Kato et al . (27) had reported that enzyme activity reached a maximum at 30 days, decreasing thereafter to about 50% of the adult activity in 150-day old rats . Further, the ability of this drug-metabolizing system to respond to the administration of a variety of "inducers," known for their potency in adult systems, was also low in fetal tissues and became more pronounced after birth (20,22,23) .…”

Section: Introductionmentioning

confidence: 99%

Ontogenetic Changes of Proteins of Endoplasmic Reticulum

Black

Bresnick

1972

The Journal of Cell Biology

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The proteins of the smooth and rough endoplasmic reticulum from fetal, immature, and adult male rats were compared after incorporation of two radioactively labeled precursors, "C-labeled amino acids and S-aminolevulinic acid 3 H by means of gel electrophoresis. The labeling patterns indicated that protein components present in two major electrophoretic bands underwent significant synthesis in fetal tissue while three actively incorporating protein bands were noted in adult tissue . Although the uptake of the amino acids-'4 C decreased for the smooth and rough elements of the endoplasmic reticulum as a whole during liver development, the qualitative patterns were not significantly different in adult and fetal livers . The over-all incorporation (disintegrations per minute per milligram protein) of the heme precursor into the smooth and rough elements also did not change with development . However, a change was noted in the distributional electrophoretic patterns with development . The estimation of molecular weight (by disc electrophoresis) and the incorporation of the heme precursor suggested the similarity of the two major protein bands to cytochrome P-450 and cytochrome b5 , components of the endoplasmic reticulum, thought to be involved in the mixed-function oxidase system . The evidence indicated that in fetal liver, at a time when the oxidase capability was low, the amino acid incorporation into these two protein groups was the same as in the adult . The incorporation of the heme moiety, however, was different, decreasing in the cytochrome b 5 region and increasing in the cytochrome P-450 region during development . These results correlate with the increase in oxidase activity associated with liver development .

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Variation in the activity of liver microsomal drug-metabolizing enzymes in rats in relation to the age

Cited by 267 publications

References 9 publications

What really declines with age?

What really declines with age?

Drug Metabolism in Tumor-Bearlng Rats

Ontogenetic Changes of Proteins of Endoplasmic Reticulum

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