Showing papers in "Basic life sciences in 1975"
TL;DR: The SOS repair hypothesis has already served as the working hypothesis for many experiments, and some speculations are presented to stimulate further discussions and experimental tests.
Abstract: A hypothesis was proposed several years ago that Escherichia coli possesses an inducible DNA repair system (“SOS repair”) which is also responsible for induced mutagenesis. Some characteristics of the SOS repair are (1) it is induced or activated following damage to DNA, (2) it requires de novo protein synthesis, (3) it requires several genetic functions of which the best-studied are recA + and lex + of E. coli, and (4) the physiological and genetic requirements for the expression of SOS repair are suspiciously similar to those necessary for the prophage induction. The SOS repair hypothesis has already served as the working hypothesis for many experiments, some of which are briefly reviewed. Also, some speculations are presented to stimulate further discussions and experimental tests.
656 citations
TL;DR: The direct photoenzymatic process is concerned in this section only with the direct photoenzyme-mediated repair of ultraviolet radiation damage to DNA.
Abstract: Photoreactivation—a reduction in the effect of ultraviolet irradiation by subsequent exposure to longer wavelengths—stems from at least two different kinds of processes. The first is direct, photoenzyme-mediated repair of ultraviolet radiation damage to DNA, while the second (“indirect photoreactivation”) is an enhancement of light-independent repairs due to physiological changes induced in cells by light.1 These two kinds of processes can be distinguished by their different wavelength and temperature dependences (Jagger and Stafford, 1965). Since indirect photoreactivation is merely one aspect of recovery through mechanisms able to act in the dark, it is best discussed in that context. We are concerned in this section only with the direct photoenzymatic process.
83 citations
TL;DR: A new exonuclease of Escherichia coli K12, ex onuclease VII, has been purified 1700-fold and characterized and is specific for single-stranded DNA and can initiated hydrolysis at both 5' and 3' termini.
Abstract: A new exonuclease of Escherichia coli K12, exonuclease VII, has been purified 1700-fold and characterized. The enzyme is specific for single-stranded DNA and can initiate hydrolysis at both 5′ and 3′ termini. It is also capable of thyminedimer excision in vitro. The limit products of the reaction are oligonucleotides, predominantly in the range of tetramers to dodecamers. DNA is hydrolyzed by the enzyme in a processive fashion. Mutants of E. coli have been isolated having reduced levels of exonuclease VII activity in crude extracts. Mapping studies place the exonuclease VII locus between 45 and 56 minutes on the E. coli K12 linkage map.
64 citations
TL;DR: A model involving recombination and DNA synthesis is described for double-strand break repair in the nuclear DNA of the yeast Saccharomyces cerevisiae and it is proposed that the corresponding gene product may be involved in double-strate break repair.
Abstract: Ionizing radiation induces double-strand breaks in the nuclear DNA of the yeast Saccharomyces cerevisiae with an efficiency of approximately 0.6 X 10(-10) breaks being repaired. Based on the efficiency of break production, the sensitivity of a rad52 mutant, and the absence of radiation-induced recombination in such a mutant, it is proposed that the corresponding gene product may be involved in double-strand break repair. A model involving recombination and DNA synthesis is described for this type of repair.
61 citations
TL;DR: The deactivation of drugs and detoxication of environmental chemicals is brought about by the metabolism of these xenobiotics by enzymes, found primarily in the liver, which decrease the lipid-solubility of these compounds and facilitate their excretion.
Abstract: The deactivation of drugs and detoxication of environmental chemicals is brought about by the metabolism of these xenobiotics by enzymes, found primarily in the liver, which decrease the lipid-solubility of these compounds and facilitate their excretion (Parke, 1968). The enzymes of mammalian liver which metabolize drugs and other xenobiotics, such as pesticides, food additives and industrial chemicals, are located predominantly in the endoplasmic reticulum and are known as the “microsomal drug-metabolizing enzymes”. These enzymes, which are responsible for oxidation, reduction and conjugation of drugs and other exogenous compounds are integral components of the membranes of the endoplasmic reticulum and although exceptionally difficult to solubilize and purify have been extensively studied using “microsomal suspensions”, consisting of the centrifuged 10,000 × g supernatant fraction, or the resuspended 100,000 × g deposit fortified with the necessary co-enzyme requirements. One notable characteristic of these hepatic microsomal enzymes is the facility with which their activities may be enhanced by enzyme induction following pretreatment with a drug or xenobiotic (Conney, 1967; Parke, 1968, 1972).
59 citations
TL;DR: The 4NQO-purine adducts and unstable 4N QO-guanine products (which release 4AQO) are, like pyrimidine dimers, repairable by excision-repair universal among E. coli, mouse, and human being, and that unexcised ones are probably the major cause of killing, mutation, and cancer.
Abstract: Excision-repair of DNA base damage produced by 4-nitroquinoline-1-oxide (4NQO) was compared in Escherichia coli, human cells, and mouse cells. Paper chromotography of acid hydrolysates of DNA extracted from cells treated with 3H-labeled 4NQO revealed four peaks; two kinds of 4NQO-guanine adduct, one kind of 4NQO-adenine adduct, and free 4-aminoquinoline-1-oxide (4AQO). About 80% of the initially formed 4NQO-purine adducts were excised from DNA in E. coli uvrA+ cells during 60 min postincubation, but not at all in uvrA- (excisionless for uv damage) cells. Normal human cells excised about 60% of 4NQO-purine adducts during 24 hr postincubation, but xeroderma pigmentosum (excisionless) cells did not. A mouse cell line susceptible to repair of 4NQO-induced pretransformational damage also showed excision-repair ability for the 4NQO adducts. From these and other results, we conclude that the 4NQO-purine adducts and unstable 4NQO-guanine products (which release 4AQO) are, like pyrimidine dimers, repairable by excision-repair universal among E. coli, mouse, and human being, and that unexcised ones are probably the major cause of killing, mutation, and cancer.
51 citations
TL;DR: The recF gene in Escherichia coli was discovered as a locus of mutations which block recombination in a RecB − recC − sbcB − strain but not in a recB + recC + sBCB + strain (Horii and Clark, 1974), and a pathway of recombination normally inhibited by ExoI which was released from inhibition by the sbc B mutations was hypothesized.
Abstract: The recF gene in Escherichia coli was discovered as a locus of mutations which block recombination in a recB − recC − sbcB − strain but not in a recB + recC + sbcB + strain (Horii and Clark, 1974). To understand the significance which was placed on this result it is necessary to know the functions of the recB, recC, and sbcB genes. The recB and recC genes determine exonuclease V (ExoV), an enzyme whose characteristics have been worked out in several laboratories (see e.g. Goldmark and Linn, 1972). Mutations in these genes inactivate ExoV and produce recombination deficiency (see e.g. Clark, 1973) which can be alleviated by sbcB mutations (Kushner et al., 1971). sbcB is thus a gene whose mutations indirectly suppress the recombination deficiency provoked by the absence of ExoV. The product of the sbcB gene is exonuclease I (ExoI) (Kushner et al., 1971, Yajko et al., 1974), an enzyme which degrades single-stranded DNA from 3′-OH termini (Lehman and Nussbaum, 1964). In recB − recC − strains it is presumably the inactivation of ExoI by sbcB mutations which leads to recombination ability, while it is the presence of ExoI which produces recombination deficiency. To explain this, Horii and Clark (1974) hypothesized a pathway of recombination normally inhibited by ExoI which was released from inhibition by the sbcB mutations. This pathway, called the RecF pathway after the recF gene, was considered to be independent of the pathway of recombination involving the recB and recC genes, the RecBC pathway.
50 citations
TL;DR: The implications of enzyme induction extend beyond alterations in rates of hepatic microsomal drug oxidation as discussed by the authors, and have been shown in man that administration of inducing agents may be associated with increased turnover of endogenous substrates such as cholesterol, vitamin D and Cortisol, with alterations in liver blood flow and bile flow, and even with amelioration of disease processes such as Gilbert's syndrome and perhaps Cushing's syndrome.
Abstract: The implications of enzyme induction extend beyond alterations in rates of hepatic microsomal drug oxidation. In the last few years it has been shown in man that administration of inducing agents may be associated with increased turnover of endogenous substrates such as cholesterol, vitamin D and Cortisol, with alterations in liver blood flow and bile flow, and even with the amelioration of disease processes such as Gilbert’s syndrome and perhaps Cushing’s syndrome.
49 citations
TL;DR: Evidence is provided showing that neither of these mechanisms accounts for UV reactivation of phage lambda, which differs from the other repair processes in that it is inducible and error-prone.
Abstract: Recovery of phage λ from ultraviolet damage can occur, in the dark, through three types of repair processes as defined by microbiological tests: (1) host-cell reactivation, (2) prophage reactivation, and (3) UV reactivation. This paper reviews the properties of the three repair processes, analyzes their dependence on the functioning of bacterial and phage genes, and discusses their relationship.
47 citations
TL;DR: Methylating agents may produce as many as nine alkylated purine and pyrimidine adducts in DNA, as well as forming phosphotriesters and inducing apurinic sites and strand breaks, which results in biological damage both in the bulk of the DNA and at DNA growing points.
Abstract: Methylating agents may produce as many as nine alkylated purine and pyrimidine adducts in DNA, as well as forming phosphotriesters and inducing apurinic sites and strand breaks. Although some of these products are formed in proportionately small amounts, there are sufficient sites affected in the DNA of a mammalian cell to make even the most minor product of potential biological significance. It is not possible to specify the exact reaction sites resulting in biological damage, but it is possible to quantitate the excision-repair of such damage both in the bulk of the DNA and at DNA growing points. Excision-repair can be measured in the bulk of the DNA by determining the specific activity of the NaC1 eluate of a benzoylated naphthoylated DEAE-cellulose column of extracts of cells after treatment and incubation in the presence of hydroxyurea and labeled thymidine. The average number of nucleotides inserted per methyl methanesulfonate-induced methyl group is 0.1, per apurinic site is 9. Repair in growing-point regions after methyl methanesulfonate treatment occurs to approximately the same extent as in the bulk of the DNA.
47 citations
TL;DR: The repair of DNA containing interstrand cross-links in Escherichia coli was studied by following the temporal sequence of DNA-related metabolic events in cells exposed to psoralen plus light, consistent with a cross-link repair mechanism involving sequential excision and recombination.
Abstract: The repair of DNA containing interstrand cross-links in Escherichia coli was studied by following the temporal sequence of DNA-related metabolic events in cells exposed to psoralen plus light. Mutations in some genes controlling replication, recombination, and repair strongly influence these specific events. Results reported here are consistent with a cross-link repair mechanism involving sequential excision and recombination.
TL;DR: Neutral and alkaline sucrose gradient sedimentation analysis was used to measure double- and single-strand breaks in the DNA of Chinese hamster ovary cells exposed to either gamma- or alpha-radiation.
Abstract: Neutral and alkaline sucrose gradient sedimentation analysis was used to measure double- and single-strand breaks in the DNA of Chinese hamster ovary (CHO) cells exposed to either gamma- or alpha-radiation. After irradiation, cells were incubated for 15-180 min to test the ability of the cell to rejoin the DNA breaks. Essentially complete rejoining was observed for single-strand breaks induced by gamma- or alpha-doses below 20 krad and for double-strand breaks induced by gamma doses below 60 krad. Approximately 80% rejoining was observed for double-strand breaks induced by alpha doses below 40 krad. At higher doses, the repair system appeared to saturate in such a way that essentially no additional breaks were rejoined.
TL;DR: Evidence from both mutational and biochemical studies shows that Neurospora has an excision-repair system for pyrimidine dimers which is very similar to the one found in Escherichia coli, and suggests that a "mutation prone" system of DNA repair exists in neurospora.
Abstract: Radiation sensitivity in the fungus Neurospora crassa is under the control of at least eight distinct loci and is also affected by cytoplasmic factors. Although radiation-sensitive mutants which affect inter- or intragenic meiotic recombination have not been isolated, mutants which are defective in the repair of pyrimidine dimers have been found. Evidence from both mutational and biochemical studies shows that Neurospora has an excision-repair system for pyrimidine dimers which is very similar to the one found in Escherichia coli. Wild-type strains excise dimers, but two mutants, uvs2 and upr1, are uv sensitive and excision defective. Like the E. coli excision-defective mutants, the Neurospora mutants show a greatly increased frequency of uv-induced mutation at low uv doses, and they do not affect recombination. However, they differ from the E. coli mutants in being significantly more sensitive to ionizing radiation than wild-type strains. A third mutant, uvs6, resembles the DNA polymerase-I- negative mutants of E. coli. It is sensitive to both uv and x-irradiation, has a wild-type pattern of uv-induced mutation, and increases spontaneous deletion frequencies. Its polymerases have not been examined. The high frequency of uv- induced mutation in excision-defective strains suggests that a ''mutation prone'' system of DNA repair existsmore » in Neurospora. (auth)« less
TL;DR: An outline review is given of the chemical properties of apurinic and apyrimidinic sites in DNA, the rate of introduction of such sites under different conditions, secondary lesions such as chain breaks, and the properties of endonucleases that specifically attack DNA at apuric sites.
Abstract: An outline review is given of the chemical properties of apurinic and apyrimidinic sites in DNA, the rate of introduction of such sites under different conditions, secondary lesions such as chain breaks, and the properties of endonucleases that specifically attack DNA at apurinic sites.
TL;DR: Mutation IexB30 has a phenotype and a genetic location very similar to zab, and it is proposed that mutations mapping between malB and metA (Mount et al., 1972) be now designated lexA.
Abstract: Bacterial mutants resistant to thymine deprivation were selected from Escherichia coli K12 (λ)+. Mutants in which wild-type λ prophage had become non-inducible after thymine starvation and/or UV irradiation were isolated (Devoret and Blanco, 1970). One of them, GY6130 (Devoret et al., 1972), has a phenotype very similar to that of AB2494 lex-1 (Howard-Flanders and Boyce, 1966). It is highly sensitive to UV light and X-rays and degrades its DNA rather extensively after irradiation (see Figs. 1 and 2); furthermore, the mutant is recombination proficient and allows the growth of phage λred gam. The mutation responsible for this phenotype has been located by Hfr × F−crosses and P1 transduction; it lies near recA between cysC and pheA. Consequently, the mutation carried by GY6130 has been named IexB30; we propose that mutations mapping between malB and metA (Mount et al., 1972) be now designated lexA. Castellazzi et al. (1972) have described, in strains carrying mutation tif (Kirby et al., 1967), a mutation they called zab that suppresses the tif phenotype. Mutation IexB30 has a phenotype and a genetic location very similar to zab. We do not know yet whether or not IexB30 and zab-53 are in the same cistron. It must be pointed out that, since zab is so close to tif,it has been diffcuil to study zab out of a tif genetic background (Castellazzi, personal communication). In contrast, the study of the genotype and phenotype of lexB30 is not subject to the same limitation.
TL;DR: Dimmer excision in mouse embryo fibroblasts declines abruptly after the fourth to the sixth subculture and is not detectable in the permanent cell line 3T3, suggesting that cessation of excision-repair may be due to genetic repression.
Abstract: Fibroblasts of mouse embryo cells from early subcultures excise pyrimidine dimers to an extent and at a rate comparable to those observed in human cells. The only apparent difference is that in primary mouse cells dimers are excised in an acid-insoluble form. Dimer excision in mouse embryo fibroblasts declines abruptly after the fourth to the sixth subculture and is not detectable in the permanent cell line 3T3. It is suggested that cessation of excision-repair may be due to genetic repression.
TL;DR: The results indicate that pyrimidine dimers are not repaired for as long as 48 hr after UV irradiation, and molecules containing pyrimidines are unable to replicate and are simply diluted out in subsequent cell divisions.
Abstract: We have assayed the ability of mammalian cells to remove pyrimidine dimers from their mitochondrial DNA. The results indicate that pyrimidine dimers are not required for as long as 48 hr after uv irradiation. Furthermore, molecules containing pyrimidine dimers are unable to replicate and are simply diluted out in subsequent cell divisions. (auth)
TL;DR: In genetically damaged cells, the pathways of survival, mutagenesis, and repair are inseparable.
Abstract: In genetically damaged cells, the pathways of survival, mutagenesis, and repair are inseparable. An irradiated or chemically treated cell, having sustained potentially lethal damage to its DNA, may or may not survive. Surviving, it may or may not have kept intact its store of genetic information. The fate of such a cell depends in part upon the nature and degree of primary DNA damage, in part upon the DNA repair systems available to the cell which are capable of neutralizing the damage, and to an important extent also upon the internal and external environmental factors which determine how effectively repair mechanisms can operate. A surviving cell may have undergone a mutation either because an unrepaired DNA lesion has generated a replication error or because an error-prone repair system has changed the base sequence in the course of restoring a viable DNA structure (see Witkin, 1969; Bridges, 1969; Kondo, 1973; Doudney, 1974).
TL;DR: Restoration of the structural integrity of the DNA by repair processes is, therefore, a vital function of every cell.
Abstract: Due to the central functional role of DNA and the fact that each cell contains only one or at the most a few copies of each chromosome, damage to DNA has more severe implications for the functional integrity of the cell than does damage to most other cellular components The chemical makeup and the large target size of chromosomal DNA make it particularly susceptible to attack by exogenous chemical and physical agents Most, if not all, reactions of exogenous agents with the sugar residues of the DNA backbone result in strand breakage While the continuity of the sugar-phosphate backbone usually remains intact for reactions involving the heterocyclic bases, such reactions may cause local distortion of the DNA conformation and of the native structure of eukaryotic chromatin The preservation of the unique three-dimensional structure of the double-stranded DNA helix appears to be a prerequisite for its unimpaired biological activity DNA base damage and concomitant helix distortion may lead to inhibition of replication and transcription and to a deterioration of the fidelity and a breakdown of the regulation of these processes Restoration of the structural integrity of the DNA by repair processes is, therefore, a vital function of every cell
TL;DR: In this paper, the SOS repair hypothesis was investigated in Escherichia coli and it was shown that incubation at 42°C stops DNA synthesis and induces lambda prophage and should also induce the postulated error-prone repair activity.
Abstract: DNA damage triggers coordinate expression of a cluster of diverse functions in Escherichia coli, including prophage induction, filamentous growth, and “aberrant” reinitiation of DNA replication at the chromosomal origin. The “SOS repair” hypothesis proposes that one of these coordinately inducible functions is an error-prone system of DNA repair (“SOS repair”) which is responsible for ultraviolet mutagenesis. In dnaB strains, incubation at 42°C stops DNA synthesis and induces lambda prophage and should, therefore, also induce the postulated error-prone repair activity. Thermal posttreatment of a dnaB uvrA derivative of E. coli B/r is found to enhance the yield of ultraviolet-light-induced mutations as much as 50-fold, while having no such effect in the dnaB + parent strain. The results support the SOS repair hypothesis. The possibility is discussed that the inducible repair system is a mutagenic DNA polymerase.
TL;DR: Haem, the iron complex of protoporphyrin, is the essential component of the many cytochromes and haem-containing enzymes involved in the important functions of electron transport, oxidation and hydroperoxidation.
Abstract: Haem, the iron complex of protoporphyrin, is the essential component of the many cytochromes and haem-containing enzymes involved in the important functions of electron transport, oxidation and hydroperoxidation. Its biosynthetic pathway has been almost completely elucidated and some insight has also been obtained into the control mechanisms which regulate its biosynthesis. Both these aspects have been reviewed extensively (Lascelles, 1964; Marks, 1969; Tait, 1968; Granick and Sassa, 1971; Marver and Schmid, 1972); only those points which will facilitate the description and understanding of the effects of drugs will be summarized here.
TL;DR: The postreplication sister exchanges in ultra-violet-irradiated bacteria result in the distribution of pyrimidine dimers between parental and daughter strands, indicating that long exchanges involving both strands of each duplex occur.
Abstract: DNA molecules that have been damaged in both strands at the same level are not subject to repair by excision but instead can be repaired through recombination with homologous molecules. Examples of two-strand damage include postreplication gaps opposite pyrimidine dimers, two-strand breaks produced by X-rays, and chemically induced interstrand cross-links. In ultraviolet-irradiated bacteria, the newly synthesized DNA is of length equal to the interdimer spacing. With continued incubation, this low-molecular-weight DNA is joined into highmolecular-weight chains (postreplication repair), a process associated with sister exchanges in bacteria. Recombination is initiated by pyrimidine dimers opposite postreplication gaps and by interstrand cross-links that have been cut by excision enzymes. The free ends at the resulting gaps presumably initiate the exchanges. Postreplication repair in Escherichia coli occurs in recB − and recC − but is greatly slowed in recF − mutants. RecB and recC are the structural genes for exonuclease V, which digests two-stranded DNA by releasing oligonucleotides first from one strand and then from the other. The postreplication sister exchanges in ultraviolet-irradiated bacteria result in the distribution of pyrimidine dimers between parental and daughter strands, indicating that long exchanges involving both strands of each duplex occur.
TL;DR: In experiments on the kinetics of strand breakage of bacterial DNA in a uvrC mutant, it was shown that the results are similar to those described earlier for the breakages of superinfecting lambda DNA.
Abstract: In experiments on the kinetics of strand breakage of bacterial DNA in a uvrC mutant, it was shown that the results are similar to those described earlier for the breakage of superinfecting lambda DNA. In the first several minutes after irradiation, more breaks appear in a uvr strain than in the uvrC mutant, but at later times the situation is reversed. The action of the uvrC gene product may be to interfere with the joining by polynucleotide ligase of the break made by the uv endonuclease. (HLW)
TL;DR: The x-ray survival responses of different ploidy rad52 strains and of half-irradiated rad52/rad52 zygotes (dominant-lethal curves) are reviewed and data from sedimentation velocity experiments which measured double-strand chromosomal DNA breakage and repair are discussed.
Abstract: The x-ray survival responses of different ploidy rad52 strains and of half-irradiated rad52/rad52 zygotes (dominant-lethal curves) are reviewed. Data from sedimentation velocity experiments which measured double-strand chromosomal DNA breakage and repair are discussed. (auth)
TL;DR: Mutations in the recA, recB, or recC genes significantly reduce the growth rate and viability of Escherichia coli.
Abstract: Mutations in the recA, recB, or recC genes significantly reduce the growth rate and viability of Escherichia coli. Cultures of rec − strains are composed of three populations of cells: viable cells, nonviable but residually dividing cells, and nonviable and nondividing cells. Nondividing cells can be separated from dividing cells by penicillin treatment and velocity sedimentation. Nondividing cells of all rec − strains are greatly reduced in their ability to synthesize DNA. recB − recC − and recA − recB − recC − nondividing cells contain DNA. This DNA is synthesized in dividing cells and segregated into the nondividing cells. recA −nondividing cells contain little or no DNA. recA − recB − recC − nondividing cell DNA accumulates single-strand breaks.
TL;DR: An endonuclease from Escherichia coli which acts specificially upon UV-irradiated DNA and is absent from the uvrA and uvrB mutants has been isolated and partially chacterized and is present in normal amounts in the urvC mutant.
Abstract: An endonuclease from Escherichia coli which acts specifically upon UV-irradiated DNA (correndonuclease II) and is absent from the uvrA and uvrB mutants has been isolated and partially characterized. The enzyme is present in normal amounts in the uvrC mutant. It elutes from phosphocellulose at about 0.25 M potassium phosphate (pH 7.5) and passes through dialysis tubing. The enzyme binds tightly to UV-irradiated DNA but does not bind to unirradiated DNA. The enzyme incises irradiated DNA to the 5′ side of a pyrimidine dimer and leaves a 5′-phosphoryl terminus which can be resealed with polynucleotide ligase. The K m of the enzyme is about 1.5 X 10-8 M dimers. Endonucleolytic activity of the enzyme is inhibited by caffeine with a K I of about 10mM.
TL;DR: Isolated nuclei from HeLa and Chinese hamster ovary cells possess the necessary enzymes for the selective excision of t' from osmium tetroxide oxidized DNA, and radiation-induced strand breakage is not required for product removal.
Abstract: The selective excision of products of the 5,6-dihydroxy-dihydrothymine type (t′) from γ-irradiated or 0s04-oxidized DNA or synthetic poly[d(A-T)] was observed with crude extracts of Escherichia coli and isolated nuclei from human carcinoma HeLa S-3 cells and Chinese hamster ovary cells
TL;DR: The present chapter will review the effects of aging on enzyme regulation; discuss the possible roles of alterations in appropriate hormonal interactions and hepatic gene expression; and suggest the manner in which these observations may provide the basis for eventual comprehension of the underlying biochemical mechanisms responsible for the physiological decline which accompanies old age.
Abstract: The single feature which probably characterizes all aging populations is a progressive impairment in the ability to adapt to environmental change. Adaptation may be expressed at a biochemical level by modifications in the rates of synthesis and degradation of enzymes, as well as by alterations in physiological activities. Thus, it was gratifying to discover that the susceptibility of at least certain enzymes to the regulation of their activities is impaired during aging. The present chapter will review the effects of aging on enzyme regulation; discuss the possible roles of alterations in appropriate hormonal interactions and hepatic gene expression; and suggest the manner in which these observations may provide the basis for eventual comprehension of the underlying biochemical mechanisms responsible for the physiological decline which accompanies old age.