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Biomedical subjects

A Seidel

Publications and source records attributed to A Seidel.

At least 127 records · Page 7Linked to original sources
PubMed1993

Loss of cathepsin B activity in alveolar macrophages after in vitro quartz phagocytosis.

Bovine alveolar macrophages were incubated up to 20 h with DQ12 quartz particles, either in untreated native form or pretreated with dipalmitoyl lecithin. The content of cathepsin B and N-acetylglucosaminidase was measured in the culture supernatant and in the cells. After incubation, a loss of about 50% of the total cathepsin B activity in the culture dish was observed, whereas no influence on total N-acetylglucosaminidase content occurred. Loss of cathepsin B activity was completely prevented by the pretreatment of quartz with the surfactant component dipalmitoyl lecithin. Similarly, a complete abrogation of the quartz effect on cathepsin B was noted when the cells were incubated with quartz in the presence of NH4Cl in order to prevent phagosome-lysosome fusion. There was also no influence on cathepsin B activity when a lysosome-rich fraction, prepared from alveolar macrophages, was incubated together with quartz. It was concluded that the reduction of cathepsin B activity was related with the intralysosomal deposition of quartz particles.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1993

Genotoxicity characteristics of reverse diol-epoxides of chrysene.

Trans-3,4-dihydroxy-3,4-dihydrochrysene (chrysene-3,4-diol), a major metabolite of chrysene, is further metabolized by rat liver enzymes to products which effectively revert the his- Salmonella typhimurium strain TA98 to histidine prototrophy, but are only weakly mutagenic in strain TA100 and in Chinese hamster V79 cells (acquisition of resistance to 6-thioguanine). The liver enzyme mediated mutagenicity of chrysene-3,4-diol is substantially enhanced in the presence of 1,1,1-trichloropropene 2,3-oxide, an inhibitor of microsomal epoxide hydrolase. The predominant metabolites of chrysene-3,4-diol, namely the anti- and syn-isomers of its 1,2-oxide (termed reverse diol-epoxides), proved to be extraordinarily effective mutagens in S.typhimurium strain TA98, but were only moderately active in strains TA100 and TA104, and in the SOS induction in Escherichia coli PQ37. These genotoxicity spectra in bacteria are completely different from those observed with the bay-region diol-epoxides of chrysene and 3-hydroxychrysene. In V79 cells, the reverse diol-epoxides formed low levels of DNA adducts and were very weak inducers of gene mutations. In M2 mouse prostate cells, however, high numbers of transformed foci were induced by chrysene-3,4-diol and its diastereomeric 1,2-oxides. Chrysene-3,4-diol was somewhat more potent than chrysene-1,2-diol. The potency of both reverse diol-epoxides was similar to that of the syn-diastereomers of the bay-region diol-epoxides of chrysene and 3-hydroxychrysene, but lower than that of their anti-diastereomers. The reverse diol-epoxides of chrysene, unlike the bay-region diol-epoxides, were inactivated by purified microsomal epoxide hydrolase. Noteworthy findings were also made with regard to the chemical stability of the diol-epoxides in buffer, determined from the decline in mutagenicity after preincubation in the absence of the target cells. Despite its lower delta Edeloc/beta value for the formation of the benzylic carbocation, anti-chrysene-3,4-diol 1,2-oxide was shorter-lived (t1/2 = 46 min) than anti-chrysene-1,2-diol 3,4-oxide (t1/2 = 74 min). Unlike other investigated diastereomeric pairs of diol-epoxides, it was also shorter-lived than its syn-diastereomer (t1/2 = 340 min).

Animals↗
PubMed1993

Sulfotransferase-mediated mutagenicity of 1-hydroxymethylpyrene and 4H-cyclopenta[def]chrysen-4-ol and its enhancement by chloride anions.

1-Hydroxymethylpyrene (HMP), a primary benzylic alcohol, and 4H-cyclopenta[def]chrysen-4-ol (OH-CPC), a secondary benzylic alcohol, were investigated for mutagenicity in Salmonella typhimurium (reversion of the his- strain TA98) in the presence of various xenobiotic-metabolizing systems. In the direct test, HMP was inactive and OH-CPC was very weakly active. In the presence of NADPH-fortified postmitochondrial fraction from rat liver (S9/NADPH), no activation of OH-CPC was observed, whereas strong mutagenic effects were elicited by HMP. In the presence of cytosol and 3'-phosphoadenosine-5'-phosphosulfate (PAPS), both alcohols were activated to potent mutagens. For equal mutagenic effects, approximately 650-fold lower concentrations of HMP were required in the cytosol/PAPS-mediated assay than in the S9/NADPH-mediated assay. The cytosol/PAPS-mediated mutagenicity of both alcohols was 3- to 4-fold enhanced, when KCl (125 mM) was present during the exposure. The authentic chloromethylarenes, 1-chloromethylpyrene and 4-chloro-4H-cyclopenta[def]chrysene, showed very strong direct mutagenicity. These results, taken together with previous findings, indicate that both primary and secondary benzylic alcohols derived from polycyclic aromatic hydrocarbons may be activated by sulfotransferases to electrophilic sulfuric acid esters, and by subsequent substitution reaction to further active species such as benzylic chlorides.

Chrysenes↗
PubMed1993

Formation of DNA adducts from 1-hydroxymethylpyrene in liver cells in vivo and in vitro.

The binding of 1-hydroxymethylpyrene (HMP) and its active metabolites, 1-hydroxymethylpyrene sulfate (SMP) and 1-chloromethylpyrene (CMP), to DNA was studied. In the liver of rats, maximum adduct levels were observed 1.5 h after i.p. injection of HMP, followed by a relatively rapid decrease. Separate exposure of different liver cell types in vitro to HMP led to high adduct levels in parenchymal cells, intermediate levels (1/10) in endothelial cells and low levels (1/200) in Kupffer cells. The adduct patterns were similar in the different cell types. The same pattern was also obtained when isolated DNA was incubated with SMP or CMP. One of the four major spots co-chromatographed on TLC with a dG adduct, one with a dA adduct and one with both dG and dA adducts. The fourth spot did not co-chromatograph with any of the adducts observed in reactions with any nucleic acid homopolymer.

Animals↗
PubMed1993

Separation of 32P-labelled nucleoside 3',5'-bisphosphate adducts by HPLC.

Relatively few reported attempts have been made to substitute HPLC for the thin-layer ion-exchange chromatography (TLC) conventionally used in the 32P-postlabelling assay. Using a reverse-phase phenyl-modified silica gel column and a gradient of methanol in 0.5 M sodium phosphate buffer (pH 2.0), we were able to improve the resolution of very similar adducts. Combined with on-line detection of Cerenkov radiation, this method allows separation of sub-femtomole quantities of 32P-labelled nucleoside 3',5'-bisphosphates modified by bulky carcinogens. Using this method, we were able to separate nine of the ten major adducts formed by reaction of the diol-epoxides of ten polycyclic aromatic hydrocarbons with DNA, and resolve different adducts formed by a single carcinogen. The major adducts formed by benzo[b]fluoranthene (BbF) or dibenz[a,h]anthracene in mouse skin in vivo have been shown to be distinct from the adducts formed directly by the bay-region diol-epoxides. The heterocyclic amines IQ and MeIQ have each been shown to form one major DNA adduct in several in vitro and in vivo systems; using HPLC we were able to resolve the two adducts formed by these food mutagens. HPLC is especially useful for the identification of adducts by means of chromatographic comparisons and in the analysis of the multiple adducts formed by complex mixtures of environmental carcinogens. The major adducts formed by benzo[a]pyrene (BaP) and BbF in mouse skin in vivo that were not resolved on TLC were well separated by HPLC and thus a major DNA adduct formed in the skin of mice treated topically with coal tar was found to be derived from BaP rather than BbF.

Animals↗
PubMed1993

Kinetics of serum 1,84 iPTH after high dose of calcitriol in uremic patients.

The temporal relation between oral administration of calcitriol and the nadir of PTH concentration is important for selecting optimal schedules of administration of calcitriol in the treatment of secondary hyperparathyroidism. To further assess this issue we examined 9 patients with preterminal renal failure (3 females, 6 males; median age 58.0 years, range 47-64, median S-Crea 4.8 mg/dl, range 3.7-6.8) with elevated baseline concentrations of 1,84 iPTH (median 46.0 pmol/l, range 18-100). After ingestion of a single oral dose of 2.0 micrograms calcitriol a transient rise in 1,25(OH)2D3 levels was seen with a peak at 6 h (from 20 pg/ml; 14-52 to 43 pg/ml; 35-102). 1,84 iPTH levels did not significantly change in the first 24 h, but were decreased significantly (p 0.01) 48 h after a single oral dose of calcitriol, the time to reach nadir varying from 24 to 96 hours. The percent decrease wa highest in patients with the highest baseline concentrations of 1,84 iPTH. Median 1,84 iPTH levels continued to remain below baseline at 48 h (25.0 pmol/l), 72 h (24.0 pmol/l) and 96 h (24.0 pmol/l) after oral calcitriol. A modest increase of S-Ca was noted which was not statistically significant. We conclude that 1. a single dose of oral calcitriol causes a delayed but long-lasting decrease of 1,84 iPTH, 2. decreased 1,84 iPTH levels persist despite return of calcitriol concentrations to baseline levels and 3. 1,84 iPTH may remain below baseline for more than 96 h.

Calcitriol↗
PubMed1992

Genetically engineered V79 Chinese hamster cells for stable expression of human cytochrome P450IA2.

V79 Chinese hamster cells were genetically engineered for stable expression of human P450IA2. Full length cDNA, encoding human P450IA2, was inserted into an SV40 early promoter containing eukaryotic expression vector and cointroduced with the selection marker neomycin phosphotransferase (conferring resistance to the neomycin derivative G418) into V79 Chinese hamster cells. The recombinant expression vector was introduced into two different V79 sublines, one expressing an endogenous acetyltransferase (V79-NH), the other not (V79-MZ). The presence of human cytochrome CYP1A2 cDNA in the G418 resistant V79 cell clones was confirmed by Southern blotting. The transcription of the cDNA into mRNA was detected by Northern blotting and the translation into an authentic cytochrome P450IA2 protein was shown by Western blotting. The enzymatic activity in these cells was determined by the cytochrome P450IA2-dependent methoxy-, ethoxy-, benzoxy-, and pentoxyresorufin dealkylation activity.

Animals↗
PubMed1992

Quinone reduction and redox cycling catalysed by purified rat liver dihydrodiol/3 alpha-hydroxysteroid dehydrogenase.

A highly active preparation of rat liver dihydrodiol/3 alpha-hydroxysteroid dehydrogenase was obtained using a newly developed, rapid purification scheme involving affinity chromatography on Red Sepharose. Depending on the coenzyme present, the purified enzyme was found to catalyse the oxidation of dihydrodiols and steroids or the reduction of substrates with carbonyl or quinone moieties. Using a wide range of synthetic quinones derived from polycyclic aromatic hydrocarbons (PAHs), we observed a pronounced regioselectivity of the quinone reductase activity. Good substrates were the o-quinones of phenanthrene, benz(a)anthracene, chrysene and benzo(a)pyrene with the quinonoid moiety in the K-region which were reduced at rates of 1-10 mumol/min.mg enzyme. 1,4-Benzoquinone, naphthalene-1,2-quinone and benz(a)anthracene-8,9-quinone were also reduced at high rates. In contrast, alkyl-substituted quinones such as duroquinone and menadione were poor substrates for the enzyme. During the enzymatic reduction of several o-quinones, but not 1,4-benzoquinone, we observed the oxidation of large amounts of NADPH and the consumption of molecular oxygen which is indicative of a redox-cycling process. Thus, the reduction of quinones of PAHs may lead to a facilitated conjugation and excretion of these highly lipophilic compounds, but may also initiate toxic processes due to the formation of reactive oxygen species.

Animals↗
PubMed1992

Involvement of cyclic guanosine monophosphate (cGMP) and cytosolic guanylate cyclase in the regulation of synaptic ribbon numbers in rat pineal gland.

In the rat pineal gland N-acetyltransferase (NAT) activity and synaptic ribbon (SR) numbers display a circadian rhythm. It is well-known that NAT activity is regulated by adrenergic mechanisms involving cyclic adenosine monophosphate (cAMP) as a second messenger. However, the mechanism involved in the regulation of SR numbers has not been established so far. In the present in vitro study, we have investigated the effects of 8-bromo-cyclic guanosine monophosphate (8-bromo-cGMP), a cyclic guanosine monophosphate (cGMP) analog, and stimulation of guanylate cyclase on SR numbers. Incubation with 8-bromo-cGMP increased SR numbers in a dose- and time-dependent manner. Further, stimulation of the cytosolic guanylate cyclase also resulted in increased SR numbers. Adrenergic agonists stimulated cGMP but did not alter SR numbers. These findings suggest that cGMP is involved as a second messenger in the regulation of SR numbers. Since the adrenergically stimulated increase in cGMP did not influence SR numbers, a non-adrenergic cGMP metabolic pathway seems to be involved in the regulation of SR numbers in the rat pineal gland.

Animals↗
PubMed1992

Training-overtraining: influence of a defined increase in training volume vs training intensity on performance, catecholamines and some metabolic parameters in experienced middle- and long-distance runners.

The influence of an increase in training volume (ITV; February 1989) vs intensity (ITI; February 1990) on performance, catecholamines, energy metabolism and serum lipids was examined in two studies on eight, and nine experienced middle- or long-distance runners; seven participated in both studies. During ITV, mean training volume was doubled from 85.9 km.week-1 (pretrial phase) to 174.6 km within 3 weeks. Some 96%-98% of the training was performed at 67 (SD 8)% of maximal performance. During ITI, speed-endurance, high-speed and interval runs increased within 3 weeks from 9 km.week-1 (pretrial phase) to 22.7 km.week-1 and the total training distance from 61.6 to 84.7 km.week-1. The ITV resulted in stagnation of running velocity at 4 mmol lactate concentration and a decrease in total running distance in the increment test. Heart rate, energy metabolic parameters, nocturnal urinary catecholamine excretion, low density, very low density lipoprotein-cholesterol and triglyceride concentrations decreased significantly; the exercise-related catecholamine plasma concentrations increased at an identical exercise intensity. The ITI produced an improvement in running velocity at 4 mmol lactate concentration and in total running distance in the increment test; heart rate, energy metabolic parameters, nocturnal catecholamine excretion, and serum lipids remained nearly constant, and the exercise-related plasma catecholamine concentrations decreased at an identical exercise intensity. The ITV-related changes in metabolism and catecholamines may have indicated an exhaustion syndrome in the majority of the athletes examined but this hypothesis has to be proven by future experimental studies.

Adult↗
PubMed1992

In vitro effects of putative neurotransmitters on synaptic ribbon numbers and N-acetyltransferase activity in the rat pineal gland.

The pineal contains a large number of classical transmitters and neuropeptides. Some of these neurochemicals are involved in the regulation of serotonin N-acetyltransferase (NAT) activity and hence in melatonin synthesis. Synaptic ribbons present in the pineal gland also exhibit a numerical day/night rhythm parallel to that of NAT activity. There is scarcity of information regarding the regulation of synaptic ribbon (SR) numbers. In the present study, we have investigated in vitro effects of a number of classical neurotransmitters and neuropeptides. NAT activity was used to monitor melatonin synthesis under the experimental conditions used. Norepinephrine (NE), Delta sleep-inducing peptide (DSIP), vasoactive intestinal polypeptide (VIP), adenosine and N-acetyl-asp-glu (NAAG) significantly increased NAT activity in rat pineal. DSIP and VIP also increase the stimulatory effect of NE on NAT activity. These neurochemicals had no effect on SR numbers. Gamma aminobutyric acid (GABA), serotonin and taurine affected neither NAT activity nor SR. Somatostatin increased SR numbers significantly, without having any effect on NAT activity. The effect of somatostatin is regarded to be pharmacologic, since rather high dosages (10(-4) M) were required to obtain a significant effect. Although somatostatin is present in the pineal and may change rhythmically, the inconsistency of the day/night rhythmicity and the lack of such a rhythm in female rats and male gerbils speaks against an important physiological role of somatostatin in regulating SR numbers.

Animals↗
PubMed1992

Glutathione conjugation of trans-3,4-dihydroxy 1,2-epoxy 1,2,3,4-tetrahydrobenzo[c]phenanthrene isomers by human glutathione transferases.

Each of the four stereoisomers of trans-3,4-dihydroxy 1,2-epoxy 1,2,3,4-tetrahydrobenzo[c]phenanthrene [(+)- and (-)-anti-BPhDE and (+)- and (-)-syn-BPhDE] has been incubated with the human glutathione transferase (GST) isoenzymes GST A1-1, GST M1-1 and GST P1-1, representing class alpha, mu and pi respectively, and glutathione (GSH). The conjugates formed were analyzed by HPLC and the results demonstrate that all GST isoenzymes catalyze the formation of GSH conjugates of all BPhDE isomers. However, a marked variation in catalytic efficiencies was observed (0.122-1.28/mM/s). These values are considerably lower than those previously estimated for the bay-region diol epoxides of benzo[a]pyrene (B[a]P) and human GSTs. The (+)-syn and (-)-anti-BPhDE (1R,2S-epoxide absolute configuration) were in general better substrates than the corresponding 1S,2R-epoxides. In accordance with previous observations with the diolepoxides of B[a]P, GST P1-1 was highly selective towards the BPhDE isomer with 4R,3S-diol 2S,1R-epoxide absolute configuration, i.e. (-)-anti-BPhDE, whereas GST A1-1 and M1-1 preferentially catalyzed the conjugation of (+)-syn-BPhDE (4R,3S-diol 2R,1S-epoxide absolute configuration). Overall, the most active isoenzyme was GST A1-1. Analysis by NMR spectroscopy of the GSH conjugates of BPhDE demonstrate that the reaction with GSH generally takes place by trans-addition of the thiol group at the benzylic C-1 carbon. The low catalytic efficiencies of human GSTs with BPhDE as compared to diolepoxides of B[a]P may be explained in part by the more crowded bay-region and substantially lower chemical reactivity (e.g. delta Edeloc/beta) of the former compounds.

Carcinogens↗
PubMed1992

Training-overtraining: performance, and hormone levels, after a defined increase in training volume versus intensity in experienced middle- and long-distance runners.

Performance and hormones were determined in eight middle- and nine long-distance runners after an increase in training volume (ITV, February 1989) or intensity (ITI, February 1990). Seven runners participated in both studies. The objective was to cause an overtraining syndrome. The mean training volume of 85.9 km week-1 increased within 3 weeks to 176.6 km week-1 during ITV and 96-98% of training volume was performed as long-distance runs at mean(s.d.) 67(8)% of maximum capacity. Speed endurance, high-speed and interval runs averaging 9 km week-1 increased within 3 weeks to 22.7 km during ITI, and the total volume increased from 61.6 to 84.7 km. A plateau in endurance performance and decrease in maximum performance occurred during ITV, probably due to overtraining, with performance incompetence over months. Nocturnal catecholamine excretion decreased markedly (47-53%), contrary to exercise-related plasma catecholamine responses, which increased. Resting and exercise-related cortisol and aldosterone levels decreased. Improvement in endurance and maximum performance occurred during ITI indicating a failure to cause an overtraining syndrome in ITI. Decrease in noctural catecholamine excretion was clearly lower (9-26%), exercise-related catecholamine responses showed a significant decrease, cortisol and aldosterone levels remained almost constant, exercise-related prolactin levels decreased slightly. There were no differences in insulin, C-peptide, free testosterone, somatotropic hormone (STH), follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), tri-iodothyronine (T3) and thyroxine (T4). The decrease in nocturnal catecholamine excretion during ITV might indicate a decrease in intrinsic sympathetic activity in exhausted sportsmen. But it remains open whether this reflected a central nervous system incompetence.

Adult↗
PubMed1992

Influence of surfactant components and exposure geometry on the effects of quartz and asbestos on alveolar macrophages.

Bovine (BAM) and rat (RAM) alveolar macrophages were incubated in vitro with DQ12 quartz or UICC chrysotile asbestos either alone or in the presence of dipalmitoyl lecithin (DPL). The reaction of the cells of both species to the untreated dust particles was similar qualitatively and quantitatively, with a loss of viability and release of lactate dehydrogenase and N-acetyl-beta-glucosaminidase after 20 hr of incubation. In the presence of DPL, the toxicity of quartz to BAM disappeared completely, whereas the protective influence of the phospholipid was distinctly diminished in the case of RAM. The presence of lavage fluid was less effective than that of pure DPL. There was no protective influence of DPL with asbestos either for BAM or for RAM. The effects of phagocytizable, suspended quartz particles were compared with the effects of the same type of particles fixed on a glass surface to exclude the possibility of phagocytosis. The effect of the suspended particles on the viability and release of enzymes was more pronounced than that of the fixed particles. On the other hand, superoxide anion production was stimulated to a much higher degree by the fixed quartz particles. This could be explained by the continuing contact of the outer cell membrane with the silica surfaces, whereas free particles were rapidly phagocytized. The release of lysosomal enzymes induced by fixed quartz particles was a secondary phenomenon following cell death.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1992

Disturbed calcium metabolism in renal failure--pathogenesis and therapeutic strategies.

Absolute or relative deficiency of 1,25(OH)2 vitamin D3 is thought to play a key role in the genesis of secondary (renal) hyperparathyroidism. Elevated concentrations of PTH and--less consistently--diminished concentrations of 1,25(OH)2 vitamin D3 are demonstrable in a considerable proportion of patients with incipient renal failure. Increased PTH concentrations counteract to some extent the trend of 1,25(OH)2 vitamin D3 production to decrease. When iPTH is elevated, prophylactic administration of 1,25(OH)2 vitamin D3 is a logical procedure, even when patients have not yet reached end-stage renal failure. With the use of low doses, the incidence of side effects is low, and excessive lowering of PTH and bone turnover presumably can be avoided. Acute administration of 1,25(OH)2 vitamin D3 to achieve brief episodes of peak plasma levels causes prolonged suppression of pre-pro-PTH mRNA in the parathyroid cell. This provides a rationale to treat symptomatic hyperparathyroidism with intermittent high dose 1,25(OH)2 vitamin D3, either per os or i.v.

Calcitriol↗
PubMed1992

Mono- and diglucuronide formation from chrysene and benzo(a)pyrene phenols by 3-methylcholanthrene-inducible phenol UDP-glucuronosyltransferase (UGT1A1).

Mono- and diphenols of chrysene and benzo(a)pyrene are suspected substrates of a 3-methylcholanthrene (MC)-inducible phenol UDP-glucuronosyltransferase (UGT1A1). Mono- and diglucuronide formation from these compounds was studied in two systems, (a) livers of MC-treated rats (homologous expression) and (b) a Chinese hamster lung fibroblast cell line (V79) containing rat UGT1A1 cDNA and stably expressing this isozyme (heterologous expression). In liver microsomes of MC-treated rats, glucuronidation of 6-hydroxychrysene was stimulated 11-fold by MC treatment. With 3,6-dihydroxychrysene, formation of its 3-hydroxy-6-monoglucuronide and of the diglucuronide was increased 24- and 310-fold, respectively. Induction factors obtained for monoglucuronide formation (but not for diglucuronide formation) were in line with published data on the increase of immunodetectable UGT1A1 protein and of its mRNA. It is suggested that the high induction factors for diglucuronide formation are the result of a combination of the induction of UGT1A1 and facilitated interaction of neighboring UGT1A1 molecules in endoplasmic reticulum membranes. Glucuronidation of 6-hydroxychrysene, 3-hydroxybenzo(a)pyrene, and 3,6-dihydroxybenzo(a)pyrene to their mono- and diglucuronides was clearly detectable in V79 cells expressing UGT1A1. However, conjugation of 3,6-dihydroxychrysene to its monoglucuronides was low and diglucuronide formation was not detectable, suggesting that UGT isozymes other than UGT1A1 are responsible for these reactions.

Animals↗
PubMed1991

Fjord- and bay-region diol-epoxides investigated for stability, SOS induction in Escherichia coli, and mutagenicity in Salmonella typhimurium and mammalian cells.

The fjord-region diol-epoxides of benzo(c)phenanthrene combine high mutagenic and carcinogenic activity with low chemical reactivity. To study whether this is a unique property of these compounds or a more general characteristic of fjord-region diol-epoxides, we have synthesized the anti- and syn-diastereomers of r-9,t-10-dihydroxy-11,12-oxy-9,10,11,12-tetrahydrobenzo(c)chrysene and r-11-t-12-dihydroxy-13,14-oxy-11,12,13,14-tetrahydrobenzo(g)chrysene. These compounds as well as the anti- and syn-diastereomers of the fjord-region diol-epoxides of benzo(c)phenanthrene and of the bay-region diol-epoxides of phenanthrene, chrysene, and benzo(a)pyrene were investigated for their half-lives in a physiological buffer, for their mutagenicity in Salmonella typhimurium (reversion of the his- strains TA97, TA98, TA100, and TA104), for induction of SOS response in Escherichia coli (SOS chromotest in strain PQ37) and for their mutagenicity in V79 Chinese hamster cells (acquisition of resistance to 6-thioguanine). All six of the investigated fjord-region diol-epoxides were more stable in physiological buffer at 37 degrees C (t1/2 greater than 2 h) than the six bay-region diol-epoxides (t1/2 = 0.011 to 1.2 h). The half-lives correlated negatively with the calculated delta Edeloc values for the formation of the benzylic carbocations, and were consistently shorter for the syn- than for the corresponding anti-diastereomer. All fjord-region diol-epoxides showed extraordinarily high activity in all six genotoxicity assays used. In mammalian cells, the anti-diol-epoxide of benzo(c)chrysene was 8.6 and 12 times more active than the anti-diol-epoxides of benzo(c)phenanthrene and benzo(a)pyrene, respectively, which were the most potent mutagens among the reference compounds. The other three newly available fjord-region diol-epoxides were also markedly more mutagenic in mammalian cells than the reference compounds. Whereas the syn-diastereomers of the simple bay-region diolepoxides were clearly less mutagenic in mammalian cells than the corresponding anti-diastereomers, the differences in potency between diastereomers were small for the fjord-region diol-epoxides. In conclusion, the diol-epoxides of benzo(c)phenanthrene are not unique in their high biological activities. The two newly available diastereomeric pairs of fjord-region diol-epoxides of benzo(g)- and benzo(c)chrysene proved to be even more active. For one of them, the diol-epoxides of benzo(g)chrysene, the delta Edeloc value for the formation of the benzylic carbocation is lower than for the benzo(c)phenanthrene diol-epoxides, for the other it is higher.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗