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D H Li

Publications and source records attributed to D H Li.

53 records · Page 3Linked to original sources
PubMed1990

Acute and long-term effects of carbon tetrachloride on DNA modifications (I-compounds) in male mouse liver.

I-compounds are recently discovered species and tissue dependent covalent DNA modifications which are detectable by the 32P-postlabeling assay for DNA adducts and tend to increase with the animal's age. The effects of the hepatocarcinogen carbon tetrachloride (CCl4) on hepatic I-compounds were studied in 10-12-month-old male ICR mice using the 32P-postlabeling assay. CCl4 was dissolved in corn oil (20%, v/v) and intraperitoneally (i.p.) injected in doses of 0.75 ml/kg (0.375 ml/100 g body weight, 20% CCl4 in corn oil) while control mice received corn oil only (0.375 ml/100 g body wt). Twenty-four h after a single injection of CCl4, the intensity of non-polar I-spots in liver DNA was significantly increased as compared with corn oil treated controls, while the level of one polar I-compound was reduced at 24 h. DNA synthesis (as indicated by [3H]thymidine incorporation) was not significantly affected at 24 h after a single dose of CCl4. To study the long-term effects of CCl4, five groups of mice were given two consecutive weekly injections of 0.75 ml/kg CCl4 (as above) and were sacrificed 1, 4, 8, 12 and 22 weeks after the second treatment. In these groups the total liver I-compound levels were reduced to 17.3-49.0% compared with corresponding controls. The maximum decline was observed at 4 weeks (17.3% of control). Comparison of thymidine incorporation showed no significant increase between control and treated liver DNAs at 1, 4 and 8 weeks after CCl4, suggesting that the decrease in I-compound levels was probably not a secondary effect of increased DNA synthesis during postnecrotic proliferation. Even though there was a trend of recovery between 8 and 22 weeks, I-compound levels still remained significantly lower at 22 weeks (49.0%). Since I-compounds appear to be normal DNA modifications, the results suggest that persistent reduction of I-compound levels contributes to the hepatocarcinogenic effect of CCl4.

Age Factors↗
PubMed1990

Age-related DNA modifications (I-compounds): modulation by physiological and pathological processes.

I-compounds are covalent DNA modifications that can be detected and measured by 32P-postlabeling assay because of their DNA-adduct like properties. They accumulate in an age-dependent, highly reproducible manner in tissue DNA of untreated animals in the absence of exogenous carcinogens and, therefore, appear to arise via the interaction of DNA with endogenous reactants formed in the course of normal metabolism. Chromatographically, they exhibit a wide range of polarities, indicative of structural diversity. In addition to age-dependent increases, I-compound profiles exhibit prominent species-, sex-, tissue- and diet-dependent qualitative and quantitative differences. Natural-ingredient (chow) diets produce qualitative differences as well as substantially higher I-compound levels in rat liver and kidney, when compared with purified diets. Modified purified diets containing high carbohydrate, protein, or fat concentrations further modulate I-compound profiles. During liver regeneration, I-compounds behave like DNA adducts rather than m5 C in that their levels are not quickly restored. Treatment of rats with the hepatocarcinogens 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), CCl4, and peroxisome proliferators as well as with a choline-devoid hepatocarcinogenic diet depressed the age-related increases of I-compound levels in liver, the target organ. Additional 32P-labeled derivatives were observed only with the peroxisome proliferators and presumably represent DNA adducts of exogenous origin. No I-compounds were detected in a series of Morris hepatomas with different degrees of differentiation. Thus, loss of I-compounds may be associated with altered gene expression/dedifferentiation. On the other hand, the age-dependent accumulation of I-compounds and their adduct-like character suggest potential relations to aging-associated dysdifferentiation and initiation of cancer. Structural complexity indicates different biological roles of I-compounds.

Aging↗
PubMed1990

Species and tissue specificities of I-compounds as contrasted with carcinogen adducts in liver, kidney and skin DNA of Sprague-Dawley rats, ICR mice and Syrian hamsters.

I-compounds are age-related bulky DNA modifications that are detected in untreated animals by 32P-postlabeling. To characterize their properties, I-compounds were compared with carcinogen-DNA adducts in liver, kidney and skin of three rodent species. Weanling female Sprague-Dawley rats, ICR mice and Syrian hamsters were fed Teklad LM485 chow diet for 3 months and raised concurrently and strictly under the same environmental conditions. Animals of each species were treated topically with 24 mumol/kg dibenz[a,j]acridine per day for 3 days, then by gavage once with a mixture of safrole and 7,12-dimethylbenz[a]anthracene (60 and 80 mumol/kg respectively), or with one of the individual carcinogens. Liver, kidney and skin DNA from carcinogen-exposed (24 h after treatment) and unexposed animals was analyzed by the monophosphate version of the 32P-postlabeling assay. While each of the three carcinogens produced qualitatively identical major adduct patterns in all samples examined, I-compounds in untreated animals showed distinct species- and tissue-dependent profiles. Rats displayed the highest I-compound levels but the lowest adduct levels in both liver and kidney among the three species. These findings demonstrate fundamental differences between I-compounds and carcinogen-DNA adducts, and support the hypothesis that I-compound formation is primarily related to species-specific, i.e. genetically determined, normal metabolic activities rather than exposure to environmental genotoxic carcinogens.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Strain differences of I-compounds in relation to organ sites of spontaneous tumorigenesis and non-neoplastic renal disease in mice.

Possible associations between the patterns and levels of I-compounds (putative endogenous, age-dependent, adduct-like DNA derivatives) and the incidence of spontaneous tumors and renal diseases in mice were investigated by 32P-postlabeling assay. Liver, lung and kidney DNAs of 8-10 month old inbred male mice of strains C57BL, C3H, CBA, A and RFM were examined. It was found that liver DNA of the C3H mouse, known to develop a high incidence of spontaneous hepatomas, and lung DNA of the A mouse, known to have a high incidence of spontaneous lung tumors, contained smaller numbers and significantly lower total levels of I-compounds as compared with the resistant C57BL mouse. Kidney DNA of C57BL, C3H and A mice presented significantly higher levels of I-compounds compared with those of CBA and RFM mice, both of which are known for exceptionally high incidences of spontaneous renal diseases. Total kidney I-compound levels in CBA and RFM mice were only 30-40% of those found in C3H, A and C57BL. Reduced I-compound levels observed in the three organs thus tended to be associated with spontaneous tumorigenesis and degenerative disease in susceptible strains, suggesting that I-compounds may be important for normal gene transcription and DNA replication. On the other hand, some of these DNA derivatives may, as adduct-like premutagenic lesions, contribute to spontaneous tumorigenesis. This was suggested by the finding that CBA mice which exhibit moderate spontaneous hepatoma incidence, had higher levels of certain I-compounds in their liver DNA although the total levels were not significantly different compared with those in C57BL mice. The observations of the present study suggest that (i) the patterns and levels of I-compounds are genetically determined and (ii) lack or excess of these DNA modifications may result in adverse health effects; however, this may not always be the case, for example, if modulating factors exist which compensate for I-compound deficiency.

Age Factors↗
PubMed1989

Antitumor agents. 100. Inhibition of human DNA topoisomerase II by cytotoxic ether and ester derivatives of podophyllotoxin and alpha-peltatin.

A principal mechanism of action of the clinical antitumor drugs etoposide (1) and teniposide (2) is the inhibition of catalytic activity of type II DNA topoisomerase and concurrent enzyme-mediated production of lethal DNA strand breaks. Substitution of the glycosidic moiety of 1 or 2 by ester and ethers, as well as the esterification and etherification of alpha-peltatin (4) including its glucosidic ethylidene and thenylidene cyclic acetals (25 and 26), has afforded compounds of much less activity than that of 1. The in vitro cytotoxicity (KB) appears to have no correlation with the inhibitory activity of the human DNA topoisomerase II.

Antineoplastic Agents, Phytogenic↗
PubMed1988

Combined modalities of resistance in etoposide-resistant human KB cell lines.

The alkaloid derivative 4'-demethylepipodophyllotoxin 9-(4,6-O-ethylidene)-beta-D-glucopyranoside (etoposide, VP-16) is believed to exert cytotoxicity by causing double-stranded DNA breaks through interruption of the breaking-resealing reaction of topoisomerase II (topo II). Thus it was conceivable that cells could become resistant to VP-16 by a decrease in topo II enzyme level, since this would lead to fewer DNA breaks. As well, given the structure of VP-16, it was also possible that a pleiotropic mechanism of resistance could decrease sensitivity to this drug. To study these possibilities, a series of VP-16-resistant human KB cell lines was established by stepwise selection. The concentrations of VP-16 required to inhibit cell proliferation by 50% in the parent line and KB/1c, KB/7d, KB/20a, and KB/40a lines were, respectively, 0.16, 4.7, 24, 31, and 47 microM. These cell lines expressed cross-resistance to 4'-(9-acridinylamino)methanesulfon-m-anisidide, doxorubicin, vincristine, and methotrexate, although the pattern of relative drug sensitivity was quite different from that of pleiotropic resistant cell lines reported elsewhere. The resistance to vincristine and methotrexate did not increase above the level of the KB/1c cells, and resistance to VP-16, doxorubicin, and especially vincristine was unstable in VP-16-resistant cells cultured in the absence of drug. Although the drug resistance marker Mr 180,000 glycoprotein could not be detected in any of our cell lines, cellular accumulation of [3H]VP-16 was reduced 50-75% in the resistant lines compared with parent KB. With increasing VP-16 resistance, the level of topo II protein, detected by antibody staining, decreased at each step of selection, concomitant with a general decrease in topo II unknotting activity. Sensitivity of the topo II unknotting assay to inhibition by VP-16 was the same for the parent and all resistant cell lines. The level of topo I activity and enzyme increased slightly in the resistant cells. Thus, these cell lines are resistant to VP-16 by virtue of at least two mechanisms: (a) reduced levels of topo II, which confers cross-resistance to other compounds which are topo II-dependent cytotoxic agents; and (b) reduced accumulation of drug, which is likely also responsible for vincristine and methotrexate resistance. However, the possible existence of other mechanisms of resistance cannot be ruled out.

DNA Damage↗
PubMed1987

Preliminary approach to the diagnosis of byssinosis.

The prevalence of byssinosis was studied in two cotton mills by a standardized questionnaire and pulmonary function measurements (forced expiratory volume in 1 second; FEV1). In mill A, the dust level was high (57-159 mg/m3). Among 90 participants, 80 were interviewed twice at an interval of 4 months, and disagreement on actual presence or absence of byssinosis was 7.5 percent. Twenty out of ninety workers had complaints of Monday symptoms and the prevalence was 22.2 percent. In mill B, the dust control (6.8 mg/m3) was relatively good. Among 173 participants from the carding room, two had complaints of Monday symptoms and the prevalence was 1.2 percent. A significant correlation was found between duration of employment and prevalence of byssinosis in mill A. FEV1 was measured in 9 byssinotics, 29 nonbyssinotics, and 30 controls before and after work on Mondays and Wednesdays. A significant decrease of 177 ml on average (7.8%) was found in byssinotics after work on Monday, whereas in nonbyssinotics, the decrease of FEV1 was nonsignificant. In controls, a slight increase in FEV1 after work was observed.

Adolescent↗
PubMedDate not supplied

Antitumor agents, 99. Synthetic ring C aromatized podophyllotoxin analogues as potential inhibitors of human DNA topoisomerase II.

Several ring C aromatized analogues of podophyllotoxin were synthesized for testing against human DNA topoisomerase II. The results indicate that aromatization of ring C gave rise to no inhibition of this enzyme at 200 microM. A comparison of the cytotoxicity among these compounds also demonstrates that a free hydroxyl group at C-4 contributes to significant cytotoxicity.

Antineoplastic Agents↗