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Human cytochromes P450 play a vital role in drug metabolism. The key step in substrate oxidation involves hydrogen atom abstraction or C=C bond addition by the oxygen atom of the Compound I intermediate. The latter has three unpaired electrons, two on the Fe-O center and one shared between the porphyrin ring and the proximal cysteinyl sulfur atom. Changes in its electronic structure have been suggested to affect reactivity. The electronic and geometric structure of Compound I in three important human subfamilies of cytochrome P450 (P450, 2C, 2B, and 3A) that are major contributors to drug metabolism is characterized here using combined quantum mechanical/molecular mechanical (QM/MM) calculations at the B3LYP:CHARMM27 level. Compound I is remarkably similar in all isoforms, with the third unpaired electron located mainly on the porphyrin ring, and this prediction is not very sensitive to details of the QM/MM methodology, such as the DFT functional, the basis set, or the size of the QM region. The presence of substrate also has no effect. The main source of variability in spin density on the cysteinyl sulfur (from 26 to 50%) is the details of the system setup, such as the starting protein geometry used for QM/MM minimization. This conformational effect is larger than the differences between human isoforms, which are therefore not distinguishable on electronic grounds, so it is unlikely that observed large differences in substrate selectivity can be explained to a large extent in these terms.

The present paper summarises the results of the project: 'Survey of Anthropogenic Sources of Dioxins and Furans in the Baltic Region'. As a part of the project, inventories have been carried out in Estonia, Latvia, Lithuania and Poland by applying the toolkit for quantification of dioxin and furan releases developed by UNEP Chemicals. The main route of direct releases to the environment is emission to air. Total emission to air from Poland was estimated at 490 (88-1,300) g I-TEQ/year, whereas the emissions from Estonia, Latvia and Lithuania were estimated as being 14 (2.4-54), 23 (2.6-63) and 17 (2.6-38) g I-TEQ, respectively. In general, the uncertainty on the estimates is very high, and recommendations regarding further development of the inventories have been made, and measures for reducing the releases have been provided.

In male Wistar rats PGF2alpha or PGE1 were injected intracerebroventricularly (icv) in a dose of 1 or 10 mug. Immediately or 1 hr after injection the locomotor and exploratory activity were measured. The levels of noradrenaline (NA), dopamine (DA) 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and acetylcholine (Ach) were measured in discrete brain areas. Both PGs applied ivc caused the depression of locomotor and exploratory activity in rats. PGE1 acted longer. Both substances but PGE1 more intensively affected the level of estimated biogenic amines in different brain structures. It is concluded that PGF2alpha and E1 are central nervous depressants. Both PGs affect neurons producing NA or 5-HT or Ach in discrete areas of brain in different manner. There is different susceptibility of brain structures on PGs action.

Rats were treated with a single dose of atropine (AT) at 5 mg/kg, or every day for 14 or 31 days with the same dose of AT, 3 h after the single dose and 24 h after the last dose of chronically administered AT, 10 micrograms of ACh was injected intracerebroventricularly, and two tests were used to examine the behavior of the animals. The tremorigenic effect of oxotremorine was also measured in mice treated with 10 mg/kg of AT for 1 month. It was shown that a single dose of AT antagonized ACh-induced behavior. The long-term treatment with AT enhanced the depressive-behavior of ACh in rats and the tremorigenic effect of oxotremorine in mice. The results suggest that long-term blockade of central cholinergic receptors induces their hypersensitivity.

Rats were treated for 14 or 30 days with 10 mg/kg sc atropine (AT) daily. 24 h after the last dose of At, 50 micrograms of muscarine (MU) was injected intracerebroventricularly (ivtr.). Long-term atropinization enhanced the behavior induced by MU. These data support our previous suggestion that chronic blockade of central muscarinic receptors induces their hypersensitivity.

The aim of this paper is to examine if central chemical sympathectomy induced by two injections of 6-hydroxydopamine (6-OHDA) in a dose of 250 mug intracerebroventricularly (i.c.v.) affects behavioral phenomena elicited by apomorphine (AP) (1 or 1.2 mg/kg i.p.) or clonidine (CL) (0.1 MG/KG, 5 Or 1 mug/kg i.p.). Experiments were carried out on male Wistar rats. The time of duration of several components of behavior and the degree of irritability of rats were measured. Moreover, open field and hole test were performed. The lower dose of AP did not affected behavior of rats. The higher dose increased the locomotor and exploratory activity of animals. 6-OHDA potentiated these effects of AP. CL (0.1 mg/kg) had a depressive effect on the rats' behavior, which was potentiated by 6-OHDA. CL (5 mug/kg) had no effect on the rats' behavior, but in a dose of 1 mug/kg caused excitatory behavior. This type of behavior was abolished by 6-OHDA. In conclusion, central chemical sympathectomy caused increased sensitivity of the central nervous system on AP. Excitatory behavioral effects of CL in low dosage may be connected with stimulation of central adrenergic receptors. Depressive behavioral effect of CL in high dosage is unspecific. Central chemical sympathectomy affects by different methods the reactivity of dopaminergic and noradrenergic neurons.

The possibility that polyphloretin phosphate (PPP) antagonizes the central effects elicited by prostaglandin (PG) E2 and F2alpha was investigated. PPP was administered i.c.v. to male Wistar rats (10 or 25 microgram) 10 or 30 min before i.c.v. injection of PGF2 or PGF2alpha (1 or 10 microgram). The duration of several component of behavior, the degree of irritability, and the rectal temperature of rats were measured; the levels of noradrenaline, dopamine, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid were measured spectrophoto-fluorometrically in discrete brain areas. PPP antagonized temperature and behaviroal changes induced in rats by PGF2alpha, but not those induced by PGE2. The magnitude of antagonism depended on the dose of PPP and on the time of the pretreatment before PGF2alpha administration. Changes in the level of biogenic amines in discrete brain areas evoked by PGs were not affected by PPP. We found that PPP antagonizes the central effects of PGF2alpha but not those of PGE2, and that changes of biogenic amines in discrete brain areas elicited by PGs are not specific.

Intraventricular injection of prostacyclin (PGI2) slightly depressed the general behavior and produced a weak hypothermia in rats. It shortened the response to a thermal nociceptive stimulus and intensified catalepsy caused by chloropromazine and haloperidol. PGI2 did not change concentration of noradrenaline, 4-hydroxytryptamine, 5-hydroxyindoleacetic acid and dopamine in different brain areas. It markedly lowered blood pressure and increased respiration. The duration of central hypotensive effect of PGI2 was shortened after 6-hydroxydopamine on 5,6-dihydroxytryptamine pretreatment. The possible involvement of a central mechanism in the hypotensive action of PGI2 requires further clarification.

Prostaglandins (PGs) E1, E2, F2alpha injected intracerebroventricularly (icv) in rats, potentiated chlorpromazine (CPZ) and pimozide (PI) catalepsy similarly. Cataleptogenic effect of haloperidol (HL) was potentiated specifically be PGE2. These phenomena were diminished by apomorphine (AP). Phenoxybenzamine (PB) diminished the potentiating effect of PGE2 and PGF2alpha on CPZ catalepsy, and strongly inhibited PGE2 the potentiating effect on HL and on PI catalepsy. Propranolol (PN) diminished the potentiating effect on HL and on PI catalepsy. Propranolol PN) diminished potentiating effect of PG on HL catalepsy and increased this effect of PGE1 on PI catalepsy. All examined PG induced catalepsy only when given in high doses (50 or 100 microgram icv). Cataleptogenic effect of PGE2 and PGF2 but not of PGE1, was evidently inhibited by AP. PGS inhibited AP stereotypy. The results suggest that the central dopaminergic receptors blockade is involved in the mechanism of potentiation of neuroleptic induced catalepsy by PGs, and that PGs are similar to neuroleptics in some aspects of central action.