JP4045640B2 - Prediction system for chemical skin irritation - Google Patents
Prediction system for chemical skin irritation Download PDFInfo
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- JP4045640B2 JP4045640B2 JP9029598A JP9029598A JP4045640B2 JP 4045640 B2 JP4045640 B2 JP 4045640B2 JP 9029598 A JP9029598 A JP 9029598A JP 9029598 A JP9029598 A JP 9029598A JP 4045640 B2 JP4045640 B2 JP 4045640B2
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- 239000000126 substance Substances 0.000 title claims description 81
- 206010040880 Skin irritation Diseases 0.000 title claims description 20
- 231100000475 skin irritation Toxicity 0.000 title claims description 20
- 230000036556 skin irritation Effects 0.000 title claims description 20
- 238000004768 lowest unoccupied molecular orbital Methods 0.000 claims description 31
- 238000004770 highest occupied molecular orbital Methods 0.000 claims description 27
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 18
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 claims description 16
- 230000007794 irritation Effects 0.000 claims description 14
- 230000009257 reactivity Effects 0.000 claims description 14
- 231100000245 skin permeability Toxicity 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 11
- 238000005192 partition Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 125000003636 chemical group Chemical group 0.000 claims description 7
- 238000004219 molecular orbital method Methods 0.000 claims description 5
- 230000001154 acute effect Effects 0.000 claims 1
- 230000000638 stimulation Effects 0.000 description 10
- 238000000034 method Methods 0.000 description 7
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000000611 regression analysis Methods 0.000 description 4
- 230000004936 stimulating effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 241000700159 Rattus Species 0.000 description 2
- -1 ketone compounds Chemical class 0.000 description 2
- 231100000108 skin corrosion Toxicity 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- 241000700198 Cavia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 238000004617 QSAR study Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
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- G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
- G16C20/30—Prediction of properties of chemical compounds, compositions or mixtures
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Description
【０００１】
【発明の属する技術分野】
本発明は、哺乳動物の皮膚に対する化学物質の刺激性を化学物質の最高被占軌道(HOMO)または最低空軌道(LUMO)の固有値を用いて予測するシステムに関する。
【０００２】
【従来の技術】
化学物質の哺乳動物の皮膚に対する刺激性を予測するために、化学物質の構造と哺乳動物の皮膚に対する刺激性との構造活性相関(QSAR)解析が試みられており、化学物質のオクタノール／水分配係数(logP)、分子容積、融点および酸解離定数(pKa)と皮膚腐食性との相関関係等がBarrat M.D.、Toxicology Letters、 75、 169-176(1995)等に報告されている。また、化学物質の経皮的電気抵抗の測定値と皮膚腐食性との相関関係等がLewis R.W. and Basketter D.A.、Current problems in dermatology、23、243-255(1995)等に報告されている。
【０００３】
【発明が解決しようとする課題】
しかしながら、Barrat M.D.、Toxicology Letters、75、169-176(1995)に記載の相関関係は非定量的であり、また、Lewis R.W. and Basketter D.A.、Current problems in dermatology、23、243-255(1995)に記載の方法では、すべての目的の化合物についてラットの皮膚を用いた実験操作が必要であるため操作が煩雑で、かつ非定量的であった。
【０００４】
【課題を解決するための手段】
このような状況下、本発明者らは、定量的でより簡便な化学物質の哺乳動物の皮膚に対する刺激性の予測システムにつき鋭意検討を行った結果、分子軌道法によって求められる化学物質の最高被占軌道(HOMO)または最低空軌道(LUMO)の固有値と、化学物質の哺乳動物の皮膚に対する刺激性の間にある種の相関関係があることを見い出し、本発明を完成した。
すなわち、本発明は、
１）化学物質の哺乳動物の皮膚に対する刺激性を予測するシステムであって、
分子軌道法によって求められた化学物質の最高被占軌道(HOMO)または最低空軌道(LUMO)の固有値の大きさに基づいてその化学物質の反応性または皮膚透過性に関するパラメーター値(Xi)を選択し、
該パラメーター値をその相関関係式 数３
【数３】
F = ai1・Xi + ai2
（式中、ai1およびai2は定数を表す。）
で演算することにより、化学物質の哺乳動物に対する皮膚刺激性ポテンシャル値(F)を決定することを特徴とする化学物質の皮膚刺激性の予測システム、
２）あらかじめ選定された複数の化学物質について、分子軌道法によって求められたそれらの化学物質の最高被占軌道(HOMO)または最低空軌道(LUMO)の固有値の大きさに基づいて群分けし、
おのおのの化学物質群について、各化学物質の反応性または皮膚透過性に関するパラメーター値(Xi)および哺乳動物の皮膚に対する刺激性ポテンシャル値(F)を１次の相関関係式 数４
【数４】
F = ai1・Xi + ai2
[式中、ai1およびai2は定数を表す。]
で重回帰解析することにより、定数ai1およびai2の値を算出し、
これらの算出値を前記の相関関係式 数４に入力して相関関係式を決定し、目的の化学物質について、最高被占軌道(HOMO)または最低空軌道(LUMO)の固有値の大きさに基づいてその化学物質が前記のいずれの化学物質群に該当するかを判断してその化学物質の反応性または皮膚透過性に関するパラメーター値(Xi)を選択し、その化学物質群について決定された上記の相関関係式に、目的の化学物質の反応性または皮膚透過性に関するパラメーター値(Xi)を入力して演算することにより、目的の化学物質の哺乳動物の皮膚に対する刺激性ポテンシャル値(F)を決定する前項１記載の化学物質の皮膚刺激性の予測システム
を提供するものである。
【０００５】
【発明の実施の形態】
以下、さらに詳細に本発明を説明する。
本発明の予測システムで用いられる、分子軌道法によって求められる化学物質の最高被占軌道(HOMO)および最低空軌道(LUMO)の固有値とは、化学物質における反応性をあらわし、最高被占軌道(HOMO)の固有値は化学物質の電子供与的反応に関与し、最低空軌道(LUMO)の固有値は化学物質の電子受容的反応に関与する。最高被占軌道(HOMO)または最低空軌道(LUMO)の固有値は、例えば、市販のプログラムMOPAC93(J.J.P. Stewart, Fujitsu Limited, Tokyo, Japan(1993))を用いてPM3ハミルトニアン法により計算することができる。
【０００６】
かかる化学物質の最高被占軌道(HOMO)または最低空軌道(LUMO)の固有値に基づき以下のようにして化学物質の刺激性を予測する。
まず、あらかじめ選定された複数の化学物質について、反応性または皮膚透過性に関するパラメーター値（Ｘi）と皮膚刺激性ポテンシャル値（Ｆ）を求める。ここで、選定する化学物質の数としては、予測精度を考慮すると５以上、多い方が望ましいが、簡便性を考慮すると５０程度までが通常の範囲である。
化学物質の反応性に関するパラメーター値としては、例えば、最高被占軌道(HOMO)の固有値、最低空軌道(LUMO)の固有値、絶対的ハードネス（Ｎ）等があげられる。絶対的ハードネス（Ｎ）は、最高被占軌道(HOMO)および最低空軌道(LUMO)の固有値を用いて、下記の式 数５から求めることができる。
【数５】
N=1/2(LUMO−HOMO)
また、化学物質の皮膚透過性に関するパラメーター値としては、例えば、オクタノール／水分配係数(logP)があげられる。logPの値は、例えば、市販のプログラムCHEMICALC(Syracuse Research Corporation)を用いて算出することができる。
化学物質の哺乳動物の皮膚に対する刺激の強さを表す刺激性ポテンシャル値（Ｆ）は、例えば、化学物質の希釈溶液をウサギ皮膚に開放適用し、適用後、刺激の度合いをDraizeの方法（Journal of Pharmacology and Experimental Therapeutics、82、377-390(1944)）に従って観察して１次刺激率（Ｉ）を求め、この１次刺激率（Ｉ）と化学物質の分子量（ＭＷ）を下記の式 数6に入力して演算することにより求めることができる。
【数６】
Ｆ＝Ｉ・ＭＷ
【０００７】
次に、これらの化学物質を、その最高被占軌道(HOMO)または最低空軌道(LUMO)の固有値の大きさに基づいて群分けし、おのおのの化学物質群について、各化学物質の反応性または皮膚透過性に関する上記のパラメーター値(Xi)および哺乳動物の皮膚に対する刺激性ポテンシャル値(F)を前記 数４に示された１次の相関関係式で重回帰解析することにより、定数ai1およびai2の値を算出する。なお、重回帰解析は、例えば、市販の重回帰プログラム(Sigma Plot、Jandel Scientific)等を用いて行うことができる。これらの算出値ai1およびai2を上記 数４に示された相関関係式に入力して相関関係式を決定する。ここで、化学物質の反応性または皮膚透過性に関する上記の種々のパラメーター値を用いて求められた相関関係式についてその相関係数を比較し、相関係数の高い相関関係式をおのおのの化学物質群について選択する。
【０００８】
さらに、目的の化学物質について、最高被占軌道(HOMO)または最低空軌道(LUMO)の固有値の大きさに基づいて、その化学物質が前記の化学物質群のいずれに該当するかを判断してその化学物質の反応性または皮膚透過性に関するパラメーター値(Xi)を選択し、その化学物質群について上記のようにして決定された相関関係式に、目的の化学物質の反応性または皮膚透過性に関するパラメータ値(Xi)を入力して演算することにより、該化学物質の哺乳動物の皮膚に対する刺激性ポテンシャル値(F)を決定することができる。なお、上記のようにして決定された相関関係式を、例えば、コンピュータープログラムに組み込み、皮膚刺激性予測装置を作製することもできる。
【０００９】
本発明のシステムは、例えば、類縁化学物質群に対して用いることができる。化学物質の最高被占軌道(HOMO)または最低空軌道(LUMO)の値の大きさにより類縁化学物質を群分けし、おのおのの化学物質群について、群別にあらかじめ選定された複数の化学物質のデータに基づいて化学物質のパラメーター値と化学物質の皮膚刺激性ポテンシャル(Ｆ)との１次の相関関係式による重回帰解析を行い、相関関係式中の定数ai1およびai2の値を算出するとよい。類縁化学物質群としては、例えば、アルコール類化合物、ケトン類化合物、アルデヒド類化合物、芳香族類化合物、エーテル類化合物等の群が挙げられ、その内分けとしてさらにハロゲン化構造を有する化合物、主として電子供与性反応を行う化合物、主として電子受容性反応を行う化合物等の群に分けることができる。また、適用可能な動物種としては、ウサギ、モルモット、ラット、マウス等があげられる。
【００１０】
【実施例】
以下、実施例により詳細に説明するが、本発明はこれに限定されるものではない。
【００１１】
実施例１
２４種のフェノール類化学物質について最高被占軌道(HOMO)および最低空軌道(LUMO)の固有値、パラメーター値(Xi)としてオクタノール／水分配係数(logP)の値および絶対的ハードネス(N)の値を算出した。結果を図１に示す。なお、上記の最高被占軌道(HOMO)および最低空軌道(LUMO)の固有値については、プログラムMOPAC93(J.J.P. Stewart, Fujitsu Limited, Tokyo, Japan(1993))でPM3ハミルトニアン法を用いて算出した。logPの値については、プログラムCHEMICALC(Syracuse Research Corporation)を用いて算出した。絶対的ハードネス(N)は、上記のHOMOおよびLUMOの固有値を下記の式 数７
【数７】
N=1/2(LUMO-HOMO)
に代入することにより算出した。
また、上記のフェノール類化学物質について33%溶液をウサギ背部皮膚に開放適用し、適用後、刺激の度合いをDraizeの方法（Journal of Pharmacology and Experimental Therapeutics、82、377-390(1944)）に従って観察し、１次刺激率(Ｉ)を求めて皮膚刺激性の評価を行った。１次刺激率(Ｉ)と化学物質の分子量(MW)を、下記の式 数８
【数８】
F=Ｉ・MW
に代入し、各化学物質の皮膚刺激性ポテンシャル実験値(F’)を得た（図１）。
つぎに、LUMOの固有値の正負により上記のフェノール類化学物質を２群にわけた。おのおのの群について重回帰プログラムを用いて、LUMOの固有値が正の群については刺激性ポテンシャル値(F’)をlogPの値の１次の相関関係式で解析した。その結果、定数ai1およびai2の値は、230および25.5であり、式 数９
【数９】
F=230logP + 25.5
(n=13、r=0.82)
で示される相関関係式が決定された。
また、LUMOの固有値が負の群については刺激性ポテンシャル値(F’)を絶対的ハードネス(N)の値の１次相関関係式で解析した。その結果、定数ai1およびai2の値は、-474および2200であり、式 数１０
【数１０】
F = -474N + 2200
(n=11、r=0.72)
で示される相関関係式が決定された。
【００１２】
実施例２
６種のフェノール類化学物質について最高被占軌道(HOMO)および最低空軌道(LUMO)の固有値、パラメーター値(X)としてオクタノール／水分配係数(logP)の値および絶対的ハードネス(N)の値を算出した。結果を図２に示す。なお、上記の最高被占軌道(HOMO)および最低空軌道(LUMO)の固有値については、プログラムMOPAC93(J.J.P. Stewart, Fujitsu Limited, Tokyo, Japan(1993))でPM3ハミルトニアン法を用いて算出した。logPの値については、プログラムCHEMICALC(Syracuse Research Corporation)を用いて算出した。絶対的ハードネス(N)は上記のHOMOおよびLUMOの固有値を用い、前記の式 数７を用いて算出した。
つぎに、LUMOの固有値の正負により上記のフェノール類化学物質を２群にわけた。LUMOの固有値の正の群については前記の式 数９に示される相関関係式で、LUMOの固有値の負の群については前記の式 数１０に示される相関関係式でそれぞれ演算することにより、化学物質の哺乳動物に対する皮膚刺激性ポテンシャル予測値(F1)を決定し、化学物質の皮膚刺激性を予測した。
また、上記のフェノール類化学物質について33%溶液をウサギ背部皮膚に開放適用し、適用後、刺激の度合いをDraizeの方法（Journal of Pharmacology and Experimental Therapeutics、82、377-390(1944)）に従って観察し、１次刺激率(Ｉ)を求めて皮膚刺激性の評価を行った。１次刺激率(Ｉ)と化学物質の分子量(MW)より、数８を用いて皮膚刺激性ポテンシャル実験値(F2)を得た（図２）。
図３に示されるように、F1とF2にはほぼ良い一致性が認められた。
【００１３】
【発明の効果】
本発明により、定量的で操作が煩雑でない、化学物質の哺乳動物の皮膚に対する刺激性の予測システムが提供可能となった。
【図面の簡単な説明】
【図１】 24種のフェノール類化学物質について、最高被占軌道(HOMO)の固有値、最低空軌道(LUMO)の固有値、オクタノール／水分配係数(logP)、１次刺激率(Ｉ)、分子量および１次刺激率(Ｉ)と分子量(MW)から算出された皮膚刺激性ポテンシャル実験値(F’)を示す。
【図２】６種のフェノール類化学物質について、最高被占軌道(HOMO)の固有値、最低空軌道(LUMO)の固有値、オクタノール／水分配係数(logP)、１次刺激率(Ｉ)、分子量および１次刺激率(Ｉ)と分子量(MW)から算出された皮膚刺激性ポテンシャル実験値(F2)を示す。
【図３】フェノール類化学物質について、本発明の予測システムにより算出された皮膚刺激性ポテンシャル予測値(F1)と皮膚刺激性ポテンシャル実験値(F2)の相関性を示す図である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a system for predicting the irritancy of a chemical substance on mammalian skin using the eigenvalue of the highest occupied orbit (HOMO) or lowest empty orbit (LUMO) of the chemical substance.
[0002]
[Prior art]
In order to predict the irritation of mammals to the skin of mammals, a structure-activity relationship (QSAR) analysis between the structure of chemicals and the irritation of mammals has been attempted. The correlation between the coefficient (logP), molecular volume, melting point, acid dissociation constant (pKa) and skin corrosivity is reported in Barrat MD, Toxicology Letters, 75, 169-176 (1995). In addition, the correlation between the measured value of transdermal electrical resistance of a chemical substance and skin corrosivity is reported in Lewis RW and Basketter DA, Current problems in dermatology, 23, 243-255 (1995).
[0003]
[Problems to be solved by the invention]
However, the correlation described in Barrat MD, Toxicology Letters, 75, 169-176 (1995) is non-quantitative and is also described in Lewis RW and Basketter DA, Current problems in dermatology, 23, 243-255 (1995). The described method is complicated and non-quantitative because all the target compounds require experimental manipulations using rat skin.
[0004]
[Means for Solving the Problems]
Under such circumstances, the present inventors have conducted intensive studies on a quantitative and simpler system for predicting the irritation of mammalian substances to the skin of mammals. We have found that there is a certain correlation between the eigenvalues of the horoscope orbit (HOMO) or lowest empty orbit (LUMO) and the irritation of chemicals to mammalian skin, thus completing the present invention.
That is, the present invention
1) A system for predicting the irritation of a chemical substance to mammalian skin,
Select the parameter value (Xi) for the reactivity or skin permeability of the chemical based on the magnitude of the eigenvalue of the highest occupied orbit (HOMO) or lowest empty orbit (LUMO) of the chemical determined by the molecular orbital method And
The parameter value is expressed by its correlation formula.
[Equation 3]
F = ai1 ・ Xi + ai2
(In the formula, ai1 and ai2 represent constants.)
A system for predicting skin irritation of a chemical substance, characterized by determining a skin irritation potential value (F) of the chemical substance to a mammal by calculating in
2) Group multiple pre-selected chemical substances based on the magnitude of eigenvalues of the highest occupied orbit (HOMO) or lowest empty orbit (LUMO) of those chemical substances determined by the molecular orbital method,
For each chemical group, the first-order correlation equation for the parameter value (Xi) for the reactivity or skin permeability of each chemical substance and the irritant potential value (F) for mammalian skin
[Expression 4]
F = ai1 ・ Xi + ai2
[Wherein ai1 and ai2 represent constants. ]
Calculate the values of constants ai1 and ai2 by performing multiple regression analysis with
These calculated values are input into the above-mentioned correlation equation (4) to determine the correlation equation, and based on the eigenvalue of the highest occupied orbit (HOMO) or lowest empty orbit (LUMO) for the target chemical substance. Judging which chemical group the chemical substance falls into, select a parameter value (Xi) relating to the reactivity or skin permeability of the chemical substance, and Enter the parameter value (Xi) related to the reactivity or skin permeability of the target chemical substance in the correlation formula, and determine the irritation potential value (F) of the target chemical substance to the mammalian skin. A system for predicting skin irritation of a chemical substance according to
[0005]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in more detail.
The eigenvalues of the highest occupied orbit (HOMO) and lowest empty orbit (LUMO) of a chemical substance obtained by the molecular orbital method used in the prediction system of the present invention represent the reactivity in the chemical substance and represent the highest occupied orbit ( The eigenvalue of (HOMO) is involved in the electron donating reaction of the chemical substance, and the eigenvalue of the lowest empty orbit (LUMO) is involved in the electron accepting reaction of the chemical substance. The eigenvalue of the highest occupied orbit (HOMO) or lowest empty orbit (LUMO) can be calculated by the PM3 Hamiltonian method using the commercially available program MOPAC93 (JJP Stewart, Fujitsu Limited, Tokyo, Japan (1993)), for example. .
[0006]
Based on the eigenvalue of the highest occupied orbit (HOMO) or lowest unoccupied orbit (LUMO) of such a chemical substance, the irritation of the chemical substance is predicted as follows.
First, parameter values (Xi) and skin irritation potential values (F) relating to reactivity or skin permeability are obtained for a plurality of chemical substances selected in advance. Here, the number of chemical substances to be selected is preferably 5 or more in consideration of prediction accuracy, but up to about 50 is a normal range in consideration of simplicity.
Examples of the parameter values relating to the reactivity of the chemical substance include eigenvalues of the highest occupied orbit (HOMO), eigenvalues of the lowest empty orbit (LUMO), and absolute hardness (N). The absolute hardness (N) can be obtained from
[Equation 5]
N = 1/2 (LUMO−HOMO)
Examples of the parameter value relating to the skin permeability of the chemical substance include octanol / water partition coefficient (logP). The value of logP can be calculated using, for example, a commercially available program CHEMICALC (Syracuse Research Corporation).
The stimulation potential value (F) representing the intensity of stimulation of the chemical substance on the mammalian skin is, for example, by applying a diluted solution of the chemical substance to the rabbit skin and applying the Draize method (Journal of Pharmacology and Experimental Therapeutics, 82, 377-390 (1944)) to obtain the primary stimulation rate (I). The primary stimulation rate (I) and the molecular weight (MW) of the chemical substance are expressed by the following formulas It can be obtained by inputting into 6 and calculating.
[Formula 6]
F = I ・ MW
[0007]
Next, these chemical substances are grouped based on the magnitude of the eigenvalue of their highest occupied orbit (HOMO) or lowest empty orbit (LUMO), and for each chemical group, the reactivity of each chemical substance or The constant values ai1 and ai2 are obtained by subjecting the above parameter values (Xi) relating to skin permeability and the stimulating potential value (F) to the skin of mammals to multiple regression analysis using the first-order correlation equation shown in Equation 4 above. Is calculated. The multiple regression analysis can be performed using, for example, a commercially available multiple regression program (Sigma Plot, Jandel Scientific). These calculated values ai1 and ai2 are input to the correlation equation shown in the above equation 4 to determine the correlation equation. Here, the correlation coefficients of the correlation equations obtained using the above-mentioned various parameter values relating to the reactivity or skin permeability of the chemical substance are compared, and the correlation equations having a high correlation coefficient are expressed for each chemical substance. Select for the group.
[0008]
Furthermore, for the target chemical substance, based on the magnitude of the eigenvalue of the highest occupied orbit (HOMO) or lowest empty orbit (LUMO), it is determined which of the above chemical substance groups the chemical substance falls into. The parameter value (Xi) related to the reactivity or skin permeability of the chemical substance is selected, and the correlation formula determined as described above for the chemical group is related to the reactivity or skin permeability of the target chemical substance. By inputting and calculating the parameter value (Xi), the stimulating potential value (F) of the chemical substance on the skin of the mammal can be determined. The correlation equation determined as described above can be incorporated into a computer program, for example, to produce a skin irritation prediction apparatus.
[0009]
The system of the present invention can be used for, for example, a group of related chemical substances. A group of related chemical substances is grouped according to the magnitude of the highest occupied orbit (HOMO) or lowest empty orbit (LUMO) of the chemical substance, and data on multiple chemical substances selected in advance for each chemical group. Based on the above, it is preferable to perform a multiple regression analysis using a first-order correlation equation between the parameter value of the chemical substance and the skin irritation potential (F) of the chemical substance, and calculate the values of the constants ai1 and ai2 in the correlation formula. The group of related chemical substances includes, for example, a group of alcohol compounds, ketone compounds, aldehyde compounds, aromatic compounds, ether compounds, and the like. It can be divided into a group such as a compound that performs a donating reaction and a compound that mainly performs an electron-accepting reaction. Applicable animal species include rabbits, guinea pigs, rats, mice and the like.
[0010]
【Example】
Hereinafter, although an example explains in detail, the present invention is not limited to this.
[0011]
Example 1
Eigenvalues of highest occupied orbit (HOMO) and lowest empty orbit (LUMO), parameter values (Xi), octanol / water partition coefficient (logP) and absolute hardness (N) values for 24 phenolic chemicals Was calculated. The results are shown in FIG. The eigenvalues of the highest occupied orbit (HOMO) and lowest empty orbit (LUMO) were calculated using the PM3 Hamiltonian method in the program MOPAC93 (JJP Stewart, Fujitsu Limited, Tokyo, Japan (1993)). The logP value was calculated using the program CHEMICALC (Syracuse Research Corporation). The absolute hardness (N) is the eigenvalue of the above HOMO and LUMO.
[Expression 7]
N = 1/2 (LUMO-HOMO)
It was calculated by substituting for.
In addition, a 33% solution of the above phenolic chemicals was applied to the rabbit's back skin, and after application, the degree of irritation was observed according to the Draize method (Journal of Pharmacology and Experimental Therapeutics, 82, 377-390 (1944)). The skin irritation was evaluated by determining the primary stimulation rate (I). The primary stimulation rate (I) and the molecular weight (MW) of a chemical substance are expressed by the following
[Equation 8]
F = I ・ MW
To obtain the experimental value (F ′) of skin irritation potential of each chemical substance (FIG. 1).
Next, the above phenolic chemicals were divided into two groups according to the positive and negative values of the eigenvalues of LUMO. Using a multiple regression program for each group, the stimulatory potential value (F ′) for the group with a positive LUMO eigenvalue was analyzed with a first-order correlation equation of the logP value. As a result, the values of the constants ai1 and ai2 are 230 and 25.5.
[Equation 9]
F = 230logP + 25.5
(n = 13, r = 0.82)
The correlation equation indicated by is determined.
In addition, for the group with a negative LUMO eigenvalue, the stimulatory potential value (F ′) was analyzed with a first-order correlation equation of the absolute hardness (N) value. As a result, the values of the constants ai1 and ai2 are −474 and 2200, and the formula 10
[Expression 10]
F = -474N + 2200
(n = 11, r = 0.72)
The correlation equation indicated by is determined.
[0012]
Example 2
Eigenvalues of highest occupied orbit (HOMO) and lowest empty orbit (LUMO), octanol / water partition coefficient (logP) and absolute hardness (N) as parameter values (X) for six phenolic chemicals Was calculated. The results are shown in FIG. The eigenvalues of the highest occupied orbit (HOMO) and lowest empty orbit (LUMO) were calculated using the PM3 Hamiltonian method in the program MOPAC93 (JJP Stewart, Fujitsu Limited, Tokyo, Japan (1993)). The logP value was calculated using the program CHEMICALC (Syracuse Research Corporation). The absolute hardness (N) was calculated by using the
Next, the above phenolic chemicals were divided into two groups according to the positive and negative values of the eigenvalues of LUMO. The positive group of LUMO eigenvalues is calculated using the correlation equation shown in
In addition, a 33% solution of the above phenolic chemicals was applied to the rabbit's back skin, and after application, the degree of irritation was observed according to the Draize method (Journal of Pharmacology and Experimental Therapeutics, 82, 377-390 (1944)). The skin irritation was evaluated by determining the primary stimulation rate (I). From the primary irritation rate (I) and the molecular weight (MW) of the chemical substance, the skin irritation potential experimental value (F2) was obtained using Equation 8 (FIG. 2).
As shown in FIG. 3, F1 and F2 were almost identical.
[0013]
【The invention's effect】
According to the present invention, it is possible to provide a system for predicting the irritation of a chemical substance to mammalian skin, which is quantitative and not complicated to operate.
[Brief description of the drawings]
[Figure 1] The highest occupied orbital (HOMO) eigenvalue, lowest empty orbital (LUMO) eigenvalue, octanol / water partition coefficient (logP), primary stimulation rate (I), molecular weight for 24 phenolic chemicals The skin irritation potential experimental value (F ′) calculated from the primary stimulation rate (I) and the molecular weight (MW) is shown.
[Fig.2] Eigenvalue of highest occupied orbit (HOMO), eigenvalue of lowest empty orbit (LUMO), octanol / water partition coefficient (logP), primary stimulation rate (I), molecular weight for six phenolic chemicals And the experimental value (F2) of skin irritation potential calculated from the primary irritation rate (I) and molecular weight (MW).
FIG. 3 is a diagram showing the correlation between the predicted value of skin irritation potential (F1) calculated by the prediction system of the present invention and the experimental value of skin irritation potential (F2) for phenolic chemical substances.
Claims (2)
【数１】
Ｆ＝ａｉ１・Ｘｉ＋ａｉ２
（式中、ａｉ１およびａｉ２は定数を表す。）で演算することにより、フェノール類化学物質の哺乳動物に対する皮膚刺激性ポテンシャル値（Ｆ）を決定することを特徴とするフェノール類化学物質の皮膚刺激性の予測システム。A system for predicting the irritation of phenolic chemicals to mammalian skin, which is a large eigenvalue of the highest occupied orbit (HOMO) or lowest empty orbit (LUMO) of a phenolic chemical obtained by molecular orbital method The octanol / water partition coefficient (log P) or absolute hardness (N) , which is the parameter value (Xi) for the reactivity or skin permeability of the chemical substance , is selected based on the parameter, and the parameter value is expressed by the correlation equation 1
[Expression 1]
F = ai1 · Xi + ai2
(Wherein ai1 and ai2 represent constants), the skin irritation potential value (F) of a phenolic chemical substance to a mammal is determined by calculating the skin irritation of the phenolic chemical substance Sex prediction system.
【数２】
Ｆ＝ａｉ１・Ｘｉ＋ａｉ２
［式中、ａｉ１およびａｉ２は定数を表す。］で重回帰解析することにより、定数ａｉ１およびａｉ２の値を算出し、これらの算出値を前記の相関関係式 数２に入力して相関関係式を決定し、目的のフェノール類化学物質について、最高被占軌道（ＨＯＭＯ）または最低空軌道（ＬＵＭＯ）の固有値の大きさに基づいてその化学物質が前記のいずれの化学物質群に該当するかを判断してその化学物質の反応性または皮膚透過性に関するパラメーター値（Ｘｉ）であるオクタノール／水分配係数（ｌｏｇＰ）または絶対的ハードネス（Ｎ）を選択し、その化学物質群について決定された上記の相関関係式に、目的のフェノール類化学物質の反応性または皮膚透過性に関するパラメーター値（Ｘｉ）を入力して演算することにより、目的のフェノール類化学物質の哺乳動物の皮膚に対する刺激性ポテンシャル値（Ｆ）を決定する請求項１記載のフェノール類化学物質の皮膚刺激性の予測システム。Grouping a plurality of phenolic chemical substances selected in advance based on the magnitude of eigenvalues of the highest occupied orbital (HOMO) or lowest empty orbital (LUMO) of those chemical substances determined by the molecular orbital method, for each chemical group, irritation potential to the skin of the reactive or octanol / water partition coefficient is a parameter value related to skin permeability (Xi) (logP) or absolute Hardness (N) and mammals animals each chemical The value (F) and the first-order correlation equation
[Expression 2]
F = ai1 · Xi + ai2
[Wherein, ai1 and ai2 represent constants. ], The values of the constants ai1 and ai2 are calculated, and these calculated values are input to the correlation equation 2 described above to determine the correlation equation. For the target phenolic chemical substance, Based on the magnitude of the eigenvalue of the highest occupied orbit (HOMO) or lowest empty orbit (LUMO), the chemical substance is judged as to which of the above-mentioned chemical substance groups, the reactivity of the chemical substance or skin permeation The octanol / water partition coefficient (log P) or absolute hardness (N) , which is the parameter value (Xi) for sex , is selected, and the above correlation equation determined for the chemical group is added to the above phenolic chemical substance. By inputting and calculating the parameter value (Xi) relating to reactivity or skin permeability, the target phenolic chemical substance is stabbed into the mammal's skin. 2. The system for predicting skin irritation of a phenolic chemical substance according to claim 1, wherein the system determines an acute potential value (F).
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